Benzothiazepine derivatives

ABSTRACT

The present invention relates to compounds of the formula (I): (wherein variable groups are as defined within) pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described

This application is a national stage entry under 35 U.S.C. § 371 ofPCT/GB01/05554, filed Dec. 17, 2001.

This invention relates to benzothiazepine derivatives, orpharmaceutically acceptable salts, solvates, solvates of such salts andprodrugs thereof. These benzothiazepines possess ileal bile acidtransport (IBAT) inhibitory activity and accordingly have value in thetreatment of disease states associated with hyperlipidaemic conditionsand they are useful in methods of treatment of a warm-blooded animal,such as man. The invention also relates to processes for the manufactureof said benzothiazepine derivatives, to pharmaceutical compositionscontaining them and to their use in the manufacture of medicaments toinhibit IBAT in a warm-blooded animal, such as man.

It is well-known that hyperlipidaemic conditions associated withelevated concentrations of total cholesterol and low-density lipoproteincholesterol are major risk factors for cardiovascular atheroscleroticdisease (for instance “Coronary Heart Disease: Reducing the Risk; aWorldwide View” Assman G., Carmnena R. Cullen P. et al; Circulation1999, 100, 1930–1938 and “Diabetes and Cardiovascular Disease: AStatement for Healthcare Professionals from the American HeartAssociation” Grundy S, Benjamin I., Burke G., et al; Circulation, 1999,100, 1134–46). Interfering with the circulation of bile acids within thelumen of the intestinal tracts is found to reduce the level ofcholesterol. Previous established therapies to reduce the concentrationof cholesterol involve, for instance, treatment with HMG-CoA reductaseinhibitors, preferably statins such as simvastatin and fluvastatin, ortreatment with bile acid binders, such as resins. Frequently used bileacid binders are for instance cholestyramine and cholestipol. Onerecently proposed therapy (“Bile Acids and Lipoprotein Metabolism: aRenaissance for Bile Acids in the Post Statin Era” Angelin B, ErikssonM, Rudling M; Current Opinion on Lipidology, 1999, 10, 269–74) involvedthe treatment with substances with an IBAT inhibitory effect.

Re-absorption of bile acid from the gastrointestinal tract is a normalphysiological process which mainly talkes place in the ileum by the IBATmechanism. Inhibitors of IBAT can be used in the treatment ofhypercholesterolaemia (see for instance “Interaction of bile acids andcholesterol with nonsystemic agents having hypocholesterolaemicproperties”, Biochemica et Biophysica Acta, 1210 (1994) 255–287). Thus,suitable compounds having such inhibitory IBAT activity are also usefulin the treatment of hyperlipidaemic conditions. Compounds possessingsuch IBAT inhibitory activity have been described, see for instancecompounds described in WO 93/16055, WO 94/18183, WO 94/18184, WO96/05188, WO 96/08484, WO 96/16051, WO 97/33882, WO98/38182, WO99/35135, WO 98/40375, WO 99/35153, WO 99/64409, WO 99/64410, WO00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE 19825804, WO00/38725, WO 00/38726, WO 00/38727, WO 00/38728, WO 00/38729, WO01/68906, and EP 0 864 582.

A further aspect of this invention relates to the use of the compoundsof the invention in the treatment of dyslipidemic conditions anddisorders such as hyperlipidaemia, hypertrigliceridemia,hyperbetalipoproteinemia (high LDL), hyperprebetalipoproteinemia (highVLDL), hyperchylomicronemia, hypolipoproteinemia, hypercholesterolemia,hyperlipoproteinemia and hypoalphalipoproteinemia (low HDL). Inaddition, these compounds are expected to be useful for the preventionand treatment of different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocyte, monocytes and/or macrophage infiltrate, intimitalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaeemic attacks.

The present invention is based on the discovery that certainbenzothiazepine compounds surprisingly inhibit IBAT. Such properties areexpected to be of value in the treatment of disease states associatedwith hyperlipidaemic conditions.

Accordingly, the present invention provides a compound of formula (I):

wherein:

R^(v) and R^(w) are independently selected from hydrogen or C₁₋₆alkyl;

R¹ and R² are independently selected from C₁₋₆alkyl;

R^(x) and R^(y) are independently selected from hydrogen or C₁₋₆alkyl,or one of R^(x) and R^(y) is hydrogen or C₁₋₆alkyl and the other ishydroxy or C₁₋₆alkoxy;

R^(z) is selected from halo, nitro, cyano, hydroxy, amino, carboxy,carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy, N—(C₁₋₆alkyl)amino,N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino, N—(C₁₋₆alkyl)carbamoyl,N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a) wherein a is 0 to 2,C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino, ureido,N′—(C₁₋₆alkyl)ureido, N—(C₁₋₆alkyl)ureido, N′,N′—(C₁₋₆alkyl)₂ureido,N′—(C₁₋₆alkyl)—N—(C₁₋₆alkyl)ureido,N′,N′—(C₁₋₆alkyl)₂—N—(C₁₋₆alkyl)ureido, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl;

v is 0–5;

one of R⁴ and R⁵ is a group of formula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

D is —O—, —N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) ishydrogen or C₆alkyl and b is 0–2;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or—P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) are independently selectedfrom C₁₋₆alkyl; or R¹¹ is a group of formula (IB):

wherein:

X is —N(R^(q)), —N(R^(q))C(O)—, —O—, and —S(O)_(a)—; wherein a is 0–2and R^(q) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl, heterocyclyl or R²³; wherein said C₁₋₄alkyl, carbocyclyl orheterocyclyl may be independently optionally substituted by one or moresubstituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or—P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selectedfrom C₁₋₆alkyl; or R¹⁵ is a group of formula (IC):

wherein:

R²⁴ is selected from hydrogen or C₁₋₄alkyl;

R²⁵ is selected from hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl orR²⁷; wherein said C₁₋₄alkyl, carbocyclyl or heterocyclyl may beindependently optionally substituted by one or more substituentsselected from R²⁸;

R²⁶ is selected from carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or—P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selectedfrom C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

z is 0–3; wherein the values of R²⁵ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N-(C₁₋₄alkyl)amino, N,N-(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷ and R¹⁸ may beindependently optionally substituted on carbon by one or more R²¹;

R¹⁹, R²⁰, R²³, R²⁷ and R²⁸ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl,heterocyclyl, sulpho, sulphino, amidino, phosphono,—P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²³, R²⁷ and R²⁸ may be independentlyoptionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the present invention there is provideda compound of formula (I′):

wherein:

R¹ and R² are independently selected from C₁₋₆alkyl;

one of R⁴ and R⁵ is a group of formula (IA′):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl) amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹²;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹³;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁴;

R⁸ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁸ isoptionally substituted by one or more substituents selected from R¹⁵;

R⁹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R⁹ is agroup of formula (IB′):

wherein:

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁶;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹⁰ may be the same or different;

m is 0–2; wherein the values of R⁸ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

R¹², R¹³ and R¹⁴ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹², R¹³ and R¹⁴ may beindependently optionally substituted on carbon by one or more R¹⁷;

R¹⁵ and R¹⁶ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulpharmoyl, sulpho, sulphino, amidino, phosphono,—P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)), —P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) are independently selectedfrom C₁₋₆alkyl; wherein R¹⁵ and R¹⁶ may be independently optionallysubstituted on carbon by one or more R¹⁸;

R¹⁷ and R¹⁸ are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

According to a further aspect of the present invention there is provideda compound of formula (I″):

wherein:

R¹ and R² are independently selected from C₁₋₆alkyl;

one of R⁴ and R⁵ is a group of formula (IA″):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸;

R⁸ is hydrogen or C₁₋₄alkyl;

R⁹ is hydrogen or C₁₋₄alkyl;

R¹⁰ is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ isoptionally substituted by one or more substituents selected from R¹⁹;

R¹¹ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(c))(OR^(d)),P(O)(OH)(OR^(c)), —P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c)and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is a groupof formula (IB″):

wherein:

X is —N(R^(q))—, —N(R^(q))C(O)—, —O—, and —S(O)_(a)—; wherein a is 0–2and R^(q) is hydrogen or C₁₋₄alkyl;

R¹² is hydrogen or C₁₋₄alkyl;

R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl or heterocyclyl; wherein R¹³ and R¹⁴ may be independentlyoptionally substituted by one or more substituents selected from R²⁰;

R¹⁵ is carboxy, sulpho, sulphino, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₆alkyl;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–3; wherein the values of R⁷ may be the same or different;

R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro, cyano,hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl,C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R⁶, R¹⁷ and R¹⁸ may be independentlyoptionally substituted on carbon by one or more R²¹;

R¹⁹ and R²⁰ are independently selected from halo, nitro, cyano, hydroxy,amino, carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl,C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl, C₁₋₄alkanoyloxy,N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino,N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a)wherein a is 0 to 2, C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl,N,N—(C₁₋₄alkyl)₂sulphamoyl, carbocyclyl, heterocyclyl, sulpho, sulphino,amidino, phosphono, —P(O)(OR^(a))(OR^(b)), —P(O)(OH)(OR^(a)),—P(O)(OH)(R^(a)) or —P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) areindependently selected from C₁₋₆alkyl; wherein R¹⁹ and R²⁰ may beindependently optionally substituted on carbon by one or more R²²;

R²¹ and R²² are independently selected from halo, hydroxy, cyano,carbamoyl, ureido, amino, nitro, carboxy, carbamoyl, mercapto,sulphamoyl, trifluoromethyl, trifluoromethoxy, methyl, ethyl, methoxy,ethoxy, vinyl, allyl, ethynyl, methoxycarbonyl, formyl, acetyl,formamido, acetylamino, acetoxy, methylamino, dimethylamino,N-methylcarbamoyl, N,N-dimethylcarbamoyl, methylthio, methylsulphinyl,mesyl, N-methylsulphamoyl and N,N-dimethylsulphamoyl;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In the following paragraphs of the description, and in the claims, wherea compound of formula (I) is referred to, it is to be understood thatthis aspect also relates to compounds of formula (I′) and compounds offormula (I″).

In addition, the skilled person will appreciate that the numberingsystem differs between compounds of formula (I) and compounds of formula(I′). The numbering system used hereinbelow refers to compounds offormula (I), but it is to be understood that these statements also applyto the corresponding values in formula (I′).

In this specification the term “alkyl” includes both straight andbranched chain alkyl groups but references to individual alkyl groupssuch as “propyl” are specific for the straight chain version only. Forexample, “C₁₋₆alkyl” includes C₁₋₄alkyl, C₁₋₃alkyl, propyl, isopropyland t-butyl. However, references to individual alkyl groups such as‘propyl’ are specific for the straight chained version only andreferences to individual branched chain alkyl groups such as ‘isopropyl’are specific for the branched chain version only. A similar conventionapplies to other radicals, for example “phenylC₁₋₆alkyl” would includephenylC₁₋₄alkyl, benzyl, 1-phenylethyl and 2-phenylethyl. The term“halo” refers to fluoro, chloro, bromo and iodo.

Where optional substituents are chosen from “one or more” groups it isto be understood that this definition includes all substituents beingchosen from one of the specified groups or the substituents being chosenfrom two or more of the specified groups.

“Heteroaryl” is a totally unsaturated, mono or bicyclic ring containing3–12 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. Preferably “heteroaryl” refers to a totally unsaturated,monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms of which at least one atom is chosen from nitrogen, sulphuror oxygen, which may, unless otherwise specified, be carbon or nitrogenlinked. In another aspect of the invention, “heteroaryl” refers to atotally unsaturated, monocyclic ring containing 5 or 6 atoms or abicyclic ring containing 8, 9 or 10 atoms of which at least one atom ischosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked. Examples and suitable, valuesof the term “heteroaryl” are thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazdlyl, isothiazolyl, triazolyl, pyranyl, indolyl, pyrimidyl,pyrazinyl, pyridazinyl, pyridyl and quinolyl. Preferably the term“heteroaryl” refers to thienyl or indolyl.

“Aryl” is a totally unsaturated, mono or bicyclic carbon ring thatcontains 3–12 atoms. Preferably “aryl” is a monocyclic ring containing 5or 6 atoms or a bicyclic ring containing 9 or 10 atoms. Suitable valuesfor “aryl” include phenyl or naphthyl. Particularly “aryl” is phenyl.

A “heterocyclyl” is a saturated, partially saturated or unsaturated,mono or bicyclic ring containing 3–12 atoms of which at least one atomis chosen from nitrogen, sulphur or oxygen, which may, unless otherwisespecified, be carbon or nitrogen linked, wherein a —CH₂— group canoptionally be replaced by a —C(O)— or a ring sulphur atom may beoptionally oxidised to form the S-oxides. Preferably a “heterocyclyl” isa saturated, partially saturated or unsaturated, mono or bicyclic ringcontaining 5 or 6 atoms of which at least one atom is chosen fromnitrogen, sulphur or oxygen, which may, unless otherwise specified, becarbon or nitrogen linked, wherein a —CH₂— group can optionally bereplaced by a —C(O)— or a ring sulphur atom may be optionally oxidisedto form S-oxide(s). Examples and suitable values of the term“heterocyclyl” are thiazolidinyl, pyrrolidinyl, pyrrolinyl,2-pyrrolidonyl, 2,5-dioxopyrrolidinyl, 2-benzoxazolinonyl,1,1-dioxotetrahydrothienyl, 2,4-dioxoimidazolidinyl,2-oxo-1,3,4-(4-triazolinyl), 2-oxazolidinonyl, 5,6-dihydrouracilyl,1,3-benzodioxolyl, 1,2,4-oxadiazolyl, 2-azabicyclo[2.2.1]heptyl,4-thiazolidonyl, morpholino, 2-oxotetrahydrofuranyl, tetrahydrofuranyl,2,3-dihydrobenzofuranyl, benzothienyl, tetrahydropyranyl, piperidyl,1-oxo-1,3-dihydroisoindolyl, piperazinyl, thiomorpholino,1,1-dioxothiomorpholino, tetrahydropyranyl, 1,3-dioxolanyl,homopiperazinyl, thienyl, isoxazolyl, imidazolyl, pyrrolyl,thiadiazolyl, isothiazolyl, 1,2,4-triazolyl, 1,3,4-triazolyl, pyranyl,indolyl, pyrinidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl,4-pyridonyl, quinolyl and 1-isoquinolonyl.

A “carbocyclyl” is a saturated, partially saturated or unsaturated, monoor bicyclic carbon ring that contains 3–12 atoms; wherein a —CH₂— groupcan optionally be replaced by a —C(O)—. Preferably “carbocyclyl” is amonocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9or 10 atoms. Suitable values for “carbocyclyl” include cyclopropyl,cyclobutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, phenyl, naphthyl, tetralinyl, indanyl or 1-oxoindanyl.Particularly “carbocyclyl” is cyclopropyl, cyclobutyl, 1-oxocyclopentyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, phenyl or1-oxoindanyl.

An example of “C₁₋₆alkanoyloxy” and “C₁₋₄alkanoyloxy” is acetoxy.Examples of “C₁₋₆alkoxycarbonyl” and “C₁₋₄alkoxycarbonyl” includemethoxycarbonyl, ethoxycarbonyl, n- and t-butoxycarbonyl. Examples of“C₁₋₆alkoxy” and “C₁₋₄alkoxy” include methoxy, ethoxy and propoxy.Examples of “C₁₋₆alkanoylamino” and “C₁₋₄alkanoylamino” includeformamido, acetamido and propionylamino. Examples of “C₁₋₆alkylS(O)_(a)wherein a is 0 to 2” and “C₁₋₄alkylS(O)_(a) wherein a is 0 to 2” includemethylthio, ethylthio, methylsulphinyl, ethylsulphinyl, mesyl andethylsulphonyl. Examples of “C₁₋₆alkanoyl” and “C₁₋₄alanoyl” includeC₁₋₃alkanoyl, propionyl and acetyl. Examples of “N—(C₁₋₆alkyl)amino” and“N—(C₁₋₄alkyl)amino” include methylamino and ethylamino. Examples of“N,N—(C₁₋₆alkyl)₂amino” and “N,N—(C₁₋₄alkyl)₂amino” includedi-N-methylamino, di-(N-ethyl)amino and N-ethyl-N-methylamino. Examplesof “C₂₋₆alkenyl” and “C₂₋₄alkenyl” are vinyl, allyl and 1-propenyl.Examples of “C₂₋₆alkynyl” and “C₂₋₄alkynyl” are ethynyl, 1-propynyl and2-propynyl. Examples of “N—(C₁₋₆alkyl)sulphamoyl” and“N—(C₁₋₄alkyl)sulphamoyl” are N—(C₁₋₃alkyl)sulphamoyl,N—(methyl)sulphamoyl and N—(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)₂sulphamoyl” and “N—(C₁₋₄alkyl)₂sulphamoyl” areN,N—(dimethyl)sulphamoyl and N—(methyl)-N—(ethyl)sulphamoyl. Examples of“N—(C₁₋₆alkyl)carbamoyl” and “N—(C₁₋₄alkyl)carbamoyl” aremethylaminocarbonyl and ethylaminocarbonyl. Examples of“N,N—(C₁₋₆alkyl)₂carbamoyl” and “N,N—(C₁₋₄alkyl)₂carbamoyl” aredimethylaminocarbonyl and methylethylaminocarbonyl. Examples of“C₁₋₆alkoxycarbonylamino” are ethoxycarbonylamino andt-butoxycarbonylamino. Examples of “N′-(C₁₋₆alkyl)ureido” areN′-methylureido and N′-ethylureido. Examples of “N—(C₁₋₆alkyl)ureido”are N-methylureido and N-ethylureido. Examples of“N′,N′-(C₁₋₆alkyl)₂ureido are N′,N′-dimethylureido andN′-methyl-N′-ethylureido. Examples of“N′-(C₁₋₆alkyl)-N—(C₁₋₆alkyl)ureido are N′-methyl-N-methylureido andN′-propyl-N-methylureido. Examples of“N′,N′-(C₁₋₆alkyl)₂-N—(C₁₋₆alkyl)ureido areN′,N′-dimethyl-N-methylureido and N′-methyl-N′-ethyl-N-propylureido.

A suitable pharmaceutically acceptable salt of a compound of theinvention is, for example, an acid-addition salt of a compound of theinvention which is sufficiently basic, for example, an acid-additionsalt with, for example, an inorganic or organic acid, for examplehydrochloric, hydrobromic, sulphuric, phosphoric, trifluoroacetic,citric or maleic acid. In addition a suitable pharmaceuticallyacceptable salt of a compound of the invention which is sufficientlyacidic is an alkali metal salt, for example a sodium or potassium salt,an alkaline earth metal salt, for example a calcium or magnesium salt,an ammonium salt or a salt with an organic base which affords aphysiologically-acceptable cation, for example a salt with methylamine,dimethylamine, trimethylamine, piperidine, morpholine ortris-(2-hydroxyethyl)amine.

The compounds of the formula (I) may be administered in the form of apro-drug which is broken down in the human or animal body to give acompound of the formula (I). Examples of pro-drugs include in vivohydrolysable esters and in vivo hydrolysable amides of a compound of theformula (I).

An in vivo hydrolysable ester of a compound of the formula (I)containing carboxy or hydroxy group is, for example, a pharmaceuticallyacceptable ester which is hydrolysed in the human or animal body toproduce the parent acid or alcohol. Suitable pharmaceutically acceptableesters for carboxy include C₁₋₆alkoxymethyl esters for examplemethoxymethyl, C₁₋₆alkanoyloxymethyl esters for examplepivaloyloxymethyl, phthalidyl esters,C₃₋₈cycloalkoxycarbonyloxyC₁₋₆alkyl esters for example1-cyclohexylcarbonyloxyethyl; 1,3-dioxolen-2-onylmethyl esters forexample. 5-methyl-1,3-dioxolen-2-onylmethyl; andC₁₋₆alkoxycarbonyloxyethyl esters for example 1-methoxycarbonyloxyethyland may be formed at any carboxy group in the compounds of thisinvention.

An in vivo hydrolysable ester of a compound of the formula (I)containing a hydroxy group includes inorganic esters such as phosphateesters and α-acyloxyalkyl ethers and related compounds which as a resultof the in vivo hydrolysis of the ester breakdown to give the parenthydroxy group. Examples of α-acyloxyalkyl ethers include acetoxymethoxyand 2,2-dimethylpropionyloxy-methoxy. A selection of in vivohydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl,phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl(to give alkyl carbonate esters), dialkylcarbamoyl andN-(dialkylaminoethyl)-N-alkylcarbamoyl (to give carbamates),dialkylaminoacetyl and carboxyacetyl. Examples of substituents onbenzoyl include morpholino and piperazino linked from a ring nitrogenatom via a methylene group to the 3- or 4-position of the benzoyl ring.

A suitable value for an iii vivo hydrolysable amide of a compound of theformula (I) containing a carboxy group is, for example, a N—C₁₋₆alkyl orN,N-di-C₁₋₆alkyl amide such as N-methyl, N-ethyl, N-propyl,N,N-dimethyl, N-ethyl-N-methyl or N,N-diethyl amide.

Some compounds of the formula (I) may have chiral centres and/orgeometric isomeric centres (E- and Z-isomers), and it is to beunderstood that the invention encompasses all such optical,diastereoisomers and geometric isomers that possess IBAT inhibitoryactivity.

The invention relates to any and all tautomeric forms of the compoundsof the formula (I) that possess IBAT inhibitory activity.

It is also to be understood that certain compounds of the formula (I)can exist in solvated as well as unsolvated forms such as, for example,hydrated forms. It is to be understood that the invention encompassesall such solvated forms which possess IBAT inhibitory activity.

Preferred values of R¹, R², R³, R⁴, R⁵ and R⁶ are as follows. Suchvalues may be used where appropriate with any of the definitions, claimsor embodiments defined hereinbefore or hereinafter.

Preferably R^(v) and R^(w) are both hydrogen.

Preferably R¹ and R² are independently selected from C₁₋₄alkyl.

More preferably R¹ and R² are independently selected from ethyl orbutyl.

More preferably R¹ and R² are independently selected from ethyl, propylor butyl.

In one aspect of the invention particularly R¹ and R² are both butyl.

In a further aspect of the invention particularly R¹ and R² are bothpropyl.

In another aspect of the invention particularly one of R¹ and R² isethyl and the other is butyl.

Preferably R^(x) and R^(y) are independently selected from hydrogen orC₁₋₆alkyl.

More preferably R^(x) and R^(y) are both hydrogen.

Preferably R^(z) is selected from halo, amino, C₁₋₆alkyl,C₁₋₆alkoxycarbonylamino or N′—(C₁₋₆alkyl)ureido.

More preferably R^(z) is selected from chloro, amino, t-butyl,t-butoxycarbonylamino or N′-(t-butyl)ureido.

Preferably v is 0 or 1.

In one aspect of the invention, more preferably v is 0.

In one aspect of the invention, more preferably v is 1.

In one aspect of the invention preferably R⁴ is a group of formula (IA)(as depicted above).

In another aspect of the invention preferably R⁵ is a group of formula(IA) (as depicted above).

Preferably R³ and R⁶ are hydrogen.

Preferably the other of R⁴ and R⁵ that is not the group of formula (IA)is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0 to2; wherein that R⁴ or R⁵ may be optionally substituted on carbon by oneor more R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino.

More preferably the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio,isopropylthio or mesyl; wherein that R⁴ or R⁵ may be optionallysubstituted on carbon by one or more R¹⁶ wherein R¹⁶ is independentlyselected from hydroxy and N,N-dimethylamino.

Particularly the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from bromo, methoxy, isopropoxy, methylthio, ethylthio,isopropylthio, 2-hydroxyethylthio, 2-(N,N-dimethylamino)ethylthio ormesyl.

More particularly the other of R⁴ and R⁵ that is not the group offormula (IA) is methylthio.

Preferably the other of R⁴ and R⁵ that is not the group of formula (IA)is selected from hydrogen, halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) whereina is 0 to 2; wherein that R⁴ or R⁵ may be optionally substituted oncarbon by one or more R¹⁶; wherein R¹⁶ is independently selected fromhydroxy, carboxy and N,N—(C₁₋₄alkyl)₂amino.

More preferably the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio,ethylthio, isopropylthio or mesyl; wherein that R⁴ or R⁵ may beoptionally substituted on carbon by one or more R¹⁶; wherein R¹⁶ isindependently selected from hydroxy, carboxy and N,N-dimethylamino.

Particularly the other of R⁴ and R⁵ that is not the group of formula(IA) is selected from hydrogen, bromo, methoxy, isopropoxy, methylthio,carboxymethylthio, ethylthio, isopropylthio, 2-hydroxyethylthio,2-(N,N-dimethylamino)ethylthio or mesyl.

In another aspect of the invention, more preferably the other of R⁴ andR⁵ that is not the group of formula (IA) is selected from hydrogen,chloro, bromo, methoxy, isopropoxy, methylthio, ethylthio orisopropylthio; wherein that R⁴ or R⁵ may be optionally substituted oncarbon by one or more R¹⁶; wherein R¹⁶ is independently selected fromhydroxy, carboxy and N,N-dimethylamino.

In another aspect of the invention, particularly the other of R⁴ and R⁵that is not the group of formula (IA) is selected from hydrogen, chloro,bromo, methoxy, isopropoxy, methylthio, carboxymethylthio, ethylthio,isopropylthio, 2-hydroxyethylthio or 2-(N,N-dimethylamino)ethylthio.

In another aspect of the invention, more particularly the other of R⁴and R⁵ that is not the group of formula (IA) is bromo or chloro.

In another aspect of the invention; more particularly the other of R⁴and R⁵ that is not the group of formula (IA) is methoxy.

In one aspect of the invention, preferably Ring A is aryl.

In another aspect of the invention, preferably Ring A is heteroaryl.

When Ring A is aryl, preferably Ring A is phenyl.

When Ring A is heteroaryl, preferably Ring A is thienyl or indolyl.

Preferably Ring A is aryl or heteroaryl; wherein Ring A is optionallysubstituted by one or more substituents selected from R¹⁷; wherein

R¹⁷ is selected from halo, hydroxy or C₁₋₄alkyl; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein

R²¹ is selected from halo.

Preferably D is —O— or —S—.

In one aspect of the invention, more preferably D is —O—.

In one aspect of the invention, more preferably D is —S—.

More preferably Ring A is phenyl, thienyl or indolyl; wherein Ring A isoptionally substituted by one or more substituents selected from halo,hydroxy or trifluoromethyl.

Particularly Ring A is selected from phenyl, 4-hydroxyphenyl,thien-2-yl, 4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,2,3-dihydroxyphenyl or indol-3-yl.

More particularly Ring A is phenyl.

In another aspect of the invention, preferably Ring A is aryl orheteroaryl; wherein Ring A is optionally substituted by one or moresubstituents selected from R¹⁷; wherein R¹⁷ is selected from halo,hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷ may be optionallysubstituted on carbon by one or more R²¹; wherein

R²¹ is selected from halo.

In another aspect of the invention, more preferably Ring A is phenyl,thienyl or indolyl; wherein Ring A is optionally substituted by one ormore substituents selected from halo, hydroxy, methoxy ortrifluoromethyl.

In another aspect of the invention, particularly Ring A is selected fromphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl,4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,2,3-dihydroxyphenyl or indol-3-yl.

In a further aspect of the invention, particularly Ring A is selectedfrom phenyl, 4-hydroxyphenyl, 4-methoxyphenyl, thien-2-yl,4-trifluoromethylphenyl, 3-hydroxyphenyl, 2-fluorophenyl,4-fluorophenyl, 2,3-dihydroxyphenyl or indol-3-yl.

Preferably R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl.

More preferably R⁷ is hydrogen, methyl or phenyl.

Particularly R⁷ is hydrogen.

In one aspect of the invention, preferably R⁸ is hydrogen.

In another aspect of the invention, preferably R⁸ is C₁₋₄alkyl.

In another aspect of the invention, more preferably R⁸ is hydrogen ormethyl.

In one aspect of the invention, preferably R⁹ is hydrogen.

In another aspect of the invention, preferably R⁹ is C₁₋₄alkyl.

In another aspect of the invention, more preferably R⁹ is hydrogen ormethyl.

Preferably R¹⁰ is hydrogen.

In one aspect of the invention, preferably R¹¹ is carboxy, sulpho,sulphino, phosphono, —P(O)(OR^(c))(OR^(d)), —P(O)(OH)(OR^(c)),—P(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) wherein R^(c) and R^(d) areindependently selected from C₁₋₆alkyl.

In another aspect of the invention, preferably R¹¹ is a group of formula(IB) (as depicted above).

Preferably R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB)(as depicted above).

More preferably R¹¹ is carboxy, —P(O)(OH)(OEt) or a group of formula(IB) (as depicted above).

In another aspect of the invention, preferably R¹¹ is carboxy, sulpho,—P(O)(OH)(OR^(c)) wherein R^(c) is selected from C₁₋₄alkyl or a group offormula (IB) (as depicted above).

Preferably X is —NH— or —NHC(O)—.

More preferably X is —NHC(O)—.

In one aspect of the invention, preferably R¹² is hydrogen.

In another aspect of the invention, preferably R¹² is C₁₋₄alkyl.

In another aspect of the invention, more preferably R¹² is hydrogen ormethyl.

Preferably R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein

R²⁰ is hydroxy.

More preferably R¹³ is hydrogen, methyl or phenyl; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein

R²⁰ is hydroxy.

Particularly R¹³ is hydrogen, hydroxymethyl or phenyl.

More particularly R¹³ is hydrogen or hydroxymethyl.

In another aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionally substituted by oneor more substituents selected from R²; wherein

R²⁰ is hydroxy, carboxy, carbocyclyl or amino; wherein R²⁰ may beoptionally substituted on carbon by one or more R²²;

R²² is hydroxy.

In another aspect of the invention, more preferably R¹³ is hydrogen,methyl, ethyl, butyl or phenyl; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein

R²⁰ is hydroxy, carboxy, phenyl or amino; wherein R²⁰ may be optionallysubstituted on carbon by one or more R²²;

R²² is hydroxy.

In another aspect of the invention, particularly R¹³ is hydrogen,hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl or phenyl.

In a further aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionally substituted by oneor more substituents selected from R²⁰; wherein

R²⁰ is hydroxy, carboxy, carbocyclyl, heterocyclyl or amino; wherein R²⁰may be optionally substituted on carbon by one or more R²²;

R²² is hydroxy.

In a further aspect of the invention, more preferably R¹³ is hydrogen,methyl, ethyl, butyl or phenyl; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein

R²⁰ is hydroxy, carboxy, phenyl, imidazolyl or amino; wherein R²⁰ may beoptionally substituted on carbon by one or more R²²;

R²² is hydroxy.

In a further aspect of the invention, particularly R¹³ is hydrogen,hydroxymethyl, 4-aminobutyl, 2-carboxyethyl, 4-hydroxybenzyl,imidazol-5-ylmethyl or phenyl.

In another further aspect of the invention, preferably R¹³ is hydrogen,C₁₋₄alkyl, carbocyclyl or R²³; wherein R¹³ is optionally substituted byone or more substituents selected from R²⁰; wherein

R²⁰ is hydroxy, C₁₋₄alkylS(O)_(a) wherein a is 0, C₁₋₄alkoxy, amino,carbocyclyl, heterocyclyl or mercapto; wherein R²⁰ may be independentlyoptionally substituted on carbon by one or more R²²;

R²² is selected from hydroxy; and

R²³ is carboxy.

In another further aspect of the invention, more preferably R¹³ ishydrogen, methyl, ethyl, butyl or phenyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein

R²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto;wherein R²⁰ may be independently optionally substituted on carbon by oneor more R²²;

R²² is selected from hydroxy; and

R²³ is carboxy.

In another further aspect of the invention, particularly R¹³ ishydrogen, carboxy, hydroxymethyl, mercaptomethyl, methoxymethyl,methylthiomethyl, 2-methylthioethyl, 4-aminobutyl, 4-hydroxybenzyl,imidazol-5-ylmethyl or phenyl.

In an other aspect more particularly R¹³ is methylthiomethyl,methylsulphinylmethyl or methylsulphonylmethyl.

Preferably R¹⁴ is hydrogen.

In another aspect of the invention, preferably R¹⁴ is selected fromhydrogen, C₁₋₄alkyl or carbocyclyl; wherein said C₁₋₄alkyl orcarbocyclyl may be optionally substituted by one or more substituentsselected from R²⁰; and

R²⁰ is hydroxy.

In another aspect of the invention, more preferably R¹⁴ is selected fromhydrogen, methyl or phenyl; wherein said methyl or phenyl may beoptionally substituted by one or more substituents selected from R²⁰;and

R²⁰ is hydroxy.

In another aspect of the invention, particularly R¹⁴ is hydrogen, phenylor hydroxymethyl.

Particularly R¹⁵ is carboxy or sulpho.

In one aspect of the invention, more particularly R¹⁵ is carboxy inanother aspect of the invention, more particularly R¹⁵ is sulpho.

Preferably R¹⁵ is carboxy, sulpho, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁₋₄alkyl.

More preferably R¹⁵ is carboxy, sulpho, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from methyl or ethyl.

Preferably R¹⁵ is carboxy, sulpho, —P(O)(OEt)(OEt), —P(O)(OH)(OEt),—P(O)(OH)(Me) or —P(O)(OEt)(Me).

Preferably R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) wherein R^(e)and R^(f) are independently selected from C₁₋₄alkyl or R¹⁵ is a group offormula (IC) (as depicted above).

More preferably R¹⁵ is carboxy, sulpho, phosphono,—P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), P(O)(OH)(R^(e)) or_P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selectedfrom methyl or ethyl or R¹⁵ is a group of formula (IC) (as depictedabove).

Preferably R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OEt)(OEt),—P(O)(Ot-Bu)(Ot-Bu), —P(O)(OH)(OEt), —P(O)(OH)(Me) or —P(O)(OEt)(Me) orR¹⁵ is a group of formula (IC) (as depicted above).

In one aspect of the invention, preferably R¹⁵ is a group of formula(IC) (as depicted above).

In another aspect of the invention, preferably R¹⁵ is not a group offormula (IC) (as depicted above).

In one aspect of the invention, preferably R¹⁵ is carboxy.

In another aspect of the invention, preferably R¹⁵ is sulpho.

In another aspect of the invention, preferably R¹⁵ is —P(O)(OH)(OEt).

In another aspect of the invention, preferably R¹⁵ is —P(O)(OH)(Me).

In another aspect of the invention, preferably R¹⁵ is —P(O)(OEt)(Me).

In one aspect of the invention, preferably R²⁴ is hydrogen.

In another aspect of the invention, preferably R²⁴ is C₁₋₄alkyl.

Preferably R²⁵ is hydrogen.

Preferably R²⁶ is carboxy.

Preferably p is 1 or 2; wherein the values of R¹³ may be the same ordifferent.

In one aspect of the invention, more preferably p is 1.

In another aspect of the invention, more preferably p is 2; wherein thevalues of R¹³ may be the same or different.

In a further aspect of the invention, more preferably p is 3; whereinthe values of R¹³ may be the same or different.

In one aspect of the invention, preferably q is 0.

In a further aspect of the invention, preferably q is 1.

In one aspect of the invention, preferably r is 0.

In one aspect of the invention, more preferably r is 1.

In another aspect of the invention, more preferably r is 2; wherein thevalues of R¹⁴ may be the same or different.

In a further aspect of the invention, more preferably r is 3; whereinthe values of R¹⁴ may be the same or different.

Preferably m is 0.

In another aspect of the invention, preferably m is 0 or 1.

Preferably n is 1.

In another aspect of the invention, preferably n is 1 or 2.

Preferably z is 1.

The group of formula (IA′) wherein R⁷ is hydrogen, methyl or phenyl, nis 1, Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionallysubstituted by one or more substituents selected from halo, hydroxy ortrifluoromethyl, m is 0 and R⁹ is carboxy, —P(O)(OH)(OR^(c)) or a groupof formula (IB).

The group of formula (IA) wherein:

D is —O— or —S—;

Ring A is phenyl, thienyl or indolyl; wherein Ring A is optionallysubstituted by one or more substituents selected from halo, hydroxy,methoxy or trifluoromethyl;

R⁷ is hydrogen, methyl or phenyl;

R⁸ is hydrogen or methyl;

R⁹ is hydrogen or methyl;

R¹⁰ is hydrogen;

m is 0–2 wherein the values of R¹⁰ may be the same or different; and

R¹¹ is carboxy, —P(O)(O)(OEt) or a group of formula (IB) (as depicted inclaim 1);

The group of formula (IB′) wherein R¹⁰ is hydrogen, hydroxymethyl orphenyl, p is 1 or 2; wherein the values of R¹⁰ may be the same ordifferent and R¹¹ is carboxy or sulpho.

The group of formula (IB) wherein:

R¹² is hydrogen or methyl;

R¹³ is hydrogen, methyl, ethyl, butyl or phenyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;R²⁰ is hydroxy, methylthio, methoxy, amino, imidazolyl or mercapto;wherein R²⁰ may be independently optionally substituted on carbon by oneor more hydroxy; R²³ is carboxy;

X is —NH— or —NHC(O)—;

R¹⁴ is selected from hydrogen, methyl or phenyl; wherein said methyl orphenyl may be optionally substituted by one or more substituentsselected from hydroxy;

R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from methyl or ethyl or R¹⁵is a group of formula (IC) (as depicted in claim 1);

p is 1–3 wherein the values of R¹³ may be the same or different;

q is 0–1; and

r is 0–3 wherein the values of R¹⁴ may be the same or different;

The group of formula (IC) wherein

R²⁴ is hydrogen;

R²⁵ is hydrogen;

R²⁶ is carboxy; and

z is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in a further aspect of the invention, there is provided acompound of formula (I′) as depicted above wherein:

R¹ and R² are independently selected from ethyl or butyl;

R³ and R⁶ are hydrogen;

R⁴ is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0to 2; wherein that R⁴ may be optionally substituted on carbon by one ormore R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino;

R⁵ is a group of formula (IA′);

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R⁷; wherein

R¹⁷ is selected from halo, hydroxy or C₁₋₄alkyl; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein

R²¹ is selected from halo;

R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB′) (asdepicted above);

R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionallysubstituted by one or more substituents selected from R²¹; wherein

R²⁰ is hydroxy;

R¹⁵ is carboxy or sulpho;

p is 1 or 2; wherein the values of R¹³ may be the same or different;

m is 0; and

n is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional aspect of the invention, there is provided acompound of formula (I′) as depicted above wherein:

R¹ and R² are both butyl or one of R¹ and R² is ethyl and the other isbutyl;

R⁴ is methylthio;

R⁵ is a group of formula (IA′) (as depicted above);

R³ and R⁶ are hydrogen;

Ring A is phenyl;

R⁷ is hydrogen;

R¹¹ is a group of formula (IB′) (as depicted above);

R¹³ is hydrogen or hydroxymethyl;

R¹⁵ is carboxy or sulpho;

p is 1 or 2; wherein the values of R¹³ may be the same or different;

m is 0;

n is 1;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in an additional further aspect of the invention, there isprovided a compound of formula (I″) as depicted above wherein:

R¹ and R² are independently selected from ethyl or butyl;

R³ and R⁶ are hydrogen;

R⁴ is selected from halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0to 2; wherein that R⁴ may be optionally substituted on carbon by one ormore R¹⁶; wherein R¹⁶ is independently selected from hydroxy andN,N—(C₁₋₄alkyl)₂amino;

R⁵ is a group of formula (IA″);

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷;

R⁷ is hydrogen, C₁₋₄alkyl or carbocyclyl;

R⁸ is hydrogen or methyl;

R⁹ is hydrogen or methyl;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) or a group of formula (IB″) (asdepicted above);

X is —NH— or —NHC(O)—;

R¹² is hydrogen or methyl;

R¹³ is hydrogen, C₁₋₄alkyl or carbocyclyl; wherein R¹³ is optionallysubstituted by one or more substituents selected from R²⁰;

R¹⁴ is hydrogen;

R¹⁵ is carboxy or sulpho;

R¹⁷ is selected from halo, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷may be optionally substituted on carbon by one or more R²¹;

R²⁰ is hydroxy, carboxy, carbocyclyl or amino; wherein R²⁰ may beoptionally substituted on carbon by one or more R²²;

R²¹ is selected from halo;

R²² is hydroxy;

p is 1–3; wherein the values of R¹³ may be the same or different.

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different; andwherein if q is 1, r is not 0;

m is 0–2; and

n is 1–3;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

Therefore in another additional further aspect of the invention, thereis provided a compound of formula (I) as depicted above wherein:

R^(v) and R^(w) are both hydrogen;

R¹ and R² are independently selected from C₁₋₄alkyl;

R^(x) and R^(y) are both hydrogen;

R^(z) is selected from halo, amino, C₁₋₆alkyl, C₁₋₆alkoxycarbonylaminoor N′—(C₁₋₆alkyl)ureido;

v is 0 or 1;

R³ and R⁶ are hydrogen;

one of R⁴ and R⁵ is a group of formula (IA) (as depicted above) and theother is selected from hydrogen, halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a)wherein a is 0 to 2; wherein that R⁴ or R⁵ may be optionally substitutedon carbon by one or more R¹⁶; wherein R¹⁶ is independently selected fromhydroxy, carboxy and N,N—(C₁₋₄alkyl)₂amino;

D is —O— or —S—;

R⁷ is hydrogen, methyl or phenyl;

R⁸ is hydrogen or methyl;

Ring A is aryl or heteroaryl; wherein Ring A is optionally substitutedby one or more substituents selected from R¹⁷; wherein R¹⁷ is selectedfrom halo, hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷ may beoptionally substituted on carbon by one or more R²¹; wherein R²¹ isselected from halo;

R⁹ is hydrogen or methyl;

R¹⁰ is hydrogen;

R¹¹ is carboxy, —P(O)(OH)(OR^(c)) wherein R^(c) is selected fromC₁₋₄alkyl or a group of formula (IB) (as depicted above);

R¹² is hydrogen or methyl;

X is —NH— or —NHC(O)—;

R¹³ is hydrogen, C₁₋₄alkyl, carbocyclyl or R²³; wherein R¹³ isoptionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy, C₁₋₄alkylS(O)_(a) wherein a is 0, C₁₋₄alkoxy,amino, carbocyclyl, heterocyclyl or mercapto; wherein R²⁰ may beindependently optionally substituted on carbon by one or more R²²; R²²is selected from hydroxy; and R²³ is carboxy;

R¹⁴ is selected from hydrogen, C₁₋₄alkyl or carbocyclyl; wherein saidC₁₋₄alkyl or carbocyclyl may be optionally substituted by one or moresubstituents selected from R²⁰; and R²⁰ is hydroxy;

R¹⁵ is carboxy, sulpho, phosphono, —P(O)(OR^(e))(OR^(f)),—P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) whereinR^(e) and R^(f) are independently selected from C₁alkyl or R¹⁵ is agroup of formula (IC) (as depicted above);

R²⁴ is hydrogen;

R²⁵ is hydrogen;

R²⁶ is carboxy;

p is 1–3; wherein the values of R¹³ may be the same or different;

q is 0–1;

r is 0–3; wherein the values of R¹⁴ may be the same or different;

m is 0–2; wherein the values of R¹⁰ may be the same or different;

n is 1–2; wherein the values of R⁷ may be the same or different;

z is 0–1; wherein the values of R²⁵ may be the same or different;

or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of the Examples or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof.

In one aspect of the invention, there is provided a compound of formula(I) selected from Examples 8, 9, 46, 56, 59, 60, 61, 62, 66 and 69 or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

In another aspect of the invention, there is provided a compound offormula (I) which is Example 73, 74, 95, 96, 97, 98, 99 and 100 or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

In another aspect of the invention, preferred compounds of the inventionare any one of Examples 43, 50, 51 and 52 or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.

In another additional aspect of the invention, preferred compounds ofthe invention are any one of Examples 43, 46, 50, 51, 56, 58, 59, 61,62, 63, 69, 81, 83, 85, 94, 97, 98, 108, 109, 110, 111 or 117.

Preferred aspects of the invention are those which relate to thecompound of formula (I) or a pharmaceutically acceptable salt thereof.

Another aspect of the present invention provides a process for preparinga compound of formula (I) or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof which process(wherein variable groups are, unless otherwise specified, as defined informula (I)) comprises of:

-   Process 1): oxidising a benzothiazepine of formula (II):

-   Process 2): for compounds of formula (I) wherein D is —O—, —NR^(a)    or —S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group;

-   Process 3): reacting an acid of formula (Va) or (Vb):

or an activated derivative thereof; with an amine of formula (VI):

-   Process 4): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB); reacting a compound of formula (I) wherein R¹¹ is    carboxy with an amine of formula (VII):

-   Process 5): for compounds of formula (I) wherein R¹¹ is carboxy;    deprotecting a compound of formula (VIIIa):

wherein R^(p) is C₁₋₄alkyl;

-   Process 6): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and R¹⁵ is carboxy; deprotecting a compound of formula    (IXa):

wherein R^(p) is C₁₋₄alkyl;

-   Process 7) for compounds of formula (I) wherein one of R⁴ and R⁵ are    independently selected from C₁₋₄alkylthio optionally substituted on    carbon by one or more R¹⁶; reacting a compound of formula (Xa) or    (Xb):

wherein L is a displaceable group; with a thiol of formula (XI):R^(y)—H  (XI)wherein R^(y) is C₁₋₄alkylthio optionally substituted on carbon by oneor more R¹⁶;

-   Process 8) for compounds of formula (I) wherein R¹⁵ is a group of    formula (IC) reacting a compound of formula (IXa) or (IXb) wherein    R^(p) is hydrogen with a compound of formula (XII):

-   Process 9): for compounds of formula (I) wherein R¹¹ is a group of    formula (IB) and R¹⁵ is a group of formula (IC) and R²⁶ is carboxy;    deprotecting a compound of formula (XIIIa):

and R^(p) is C₁₋₄alkyl;

-   Process 10): for compounds of formula (I) wherein X is    —N(R^(q))C(O)—; reacting a compound of formula (XIVa):

with a compound of formula (XV):

and thereafter if necessary or desirable:

-   i) converting a compound of the formula (I) into another compound of    the formula (I);-   ii) removing any protecting groups;-   iii) forming a pharmaceutically acceptable salt, solvate, solvate of    such a salt or a prodrug.

The skilled person will also appreciate that similar processescorresponding to the above processes can also be used to preparecompounds of formula (I′) and compounds of formula (I″) wherein thedefinitions of the variable groups may differ.

L is a displaceable group, suitable values for L are for Example, ahalogeno or sulphonyloxy group, for Example a chloro, bromo,methanesulphonyloxy or toluene-4-sulphonyloxy group.

R^(p) is C₁₋₄alkyl. Preferably R^(p) is methyl or ethyl. More preferablyR^(p) is methyl.

Specific reaction conditions for the above reactions are as follows.

-   Process 1): Benzothiazepines of formula (II) may be oxidised under    standard sulphur oxidation conditions; for Example using hydrogen    peroxide and trifluoroacetic acid at a temperature in the range of    0° C. to reflux, preferably at or near room temperature.

Compounds of formula (II) may be prepared according to Scheme I forcompounds of formula (I) wherein R^(x) and R^(y) are hydrogen. Theskilled man will appreciate that where R^(x) and R^(y) are not bothhydrogen the following synthetic route needs to be manipulated usingprocedures known to the skilled person.

wherein L is a displaceable group as defined above, and Y is adisplaceable group, for Example halo.

Compounds of formula (IIa) and (IIc) are commercially availablecompounds, or they are known in the literature, or they are prepared bystandard processes known in the art.

-   Process 2): Alcohols of formula (IIIa) or (IIIb) may be reacted with    compounds of formula (IV) in the presence of a base for Example an    inorganic base such as sodium carbonate, or an organic base such as    Hunigs base, in the presence of a suitable solvent such as    acetonitrile, dichloromethane or tetrahydrofuran at a temperature in    the range of 0° C. to reflux, preferably at or near reflux.

Compounds of formula (IIIa) or (IIIb) may be prepared in a similarmanner to compounds of formula (II) (but wherein R⁴ or R⁵ is hydroxy)followed by the oxidation step of Process 1).

Compounds of formula (IV) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

-   Process 3), Process 4, Process 8) and Process 10): Acids and amines    may be coupled together in the presence of a suitable coupling    reagent. Standard peptide coupling reagents known in the art can be    employed as suitable coupling reagents, or for Example    carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the    presence of a catalyst such as dimethylaminopyridine or    4-pyrrolidinopyridine, optionally in the presence of a base for    Example triethylamine, pyridine, or 2,6-di-alkyl-pyridines such as    2,6-lutidine or 2,6-di-tert-butylpyridine. Suitable solvents include    dimethylacetamide, dichloromethane, benzene, tetrahydrofuran and    dimethylformamide. The coupling reaction may conveniently be    performed at a temperature in the range of −40 to 40° C.

Suitable activated acid derivatives include acid halides, for Exampleacid chlorides, and active esters, for Example pentafluorophenyl esters.The reaction of these types of compounds with amines is well known inthe art, for Example they may be reacted in the presence of a base, suchas those described above, and in a suitable solvent, such as thosedescribed above. The reaction may conveniently be performed at atemperature in the range of −40 to 40° C.

Compounds of formula (Va) or (Vb) wherein D is —O—, —NR^(a)— or —S— maybe prepared according to Scheme 2:

wherein L is a displaceable group as defined above.

Compounds of formula (Va) and (Vb) where D is —SO— or —SO₂— may beprepared by oxidising the resulting compounds of formula (Va) and (Vb)from Scheme 2 where D is —S—.

Compounds of formula (Va) or (Vb) wherein D is —CH₂— may be preparedaccording to Scheme 3.

Compounds of formula (XIVa) or (XIVa) may be prepared by any of theprocesses described herein where R¹¹ is a group of formula (IB) butwherein (IB) is a group of formula (XVI):

Compounds of formula (Vc), (VI), (VII), (XII), (XV) and (XVI) arecommercially available compounds, or they are known in the literature,or they are prepared by standard processes known in the art.

-   Process 5), Process 6) and Process 9): Esters of formula (VIIIa),    (VIIIb), (IXa), (IXb) (XIIIa) and (XIIIb) may be deprotected under    standard conditions such as those described below, for Example they    may be deprotected with sodium hydroxide in methanol at room    temperature.

Esters of formula (VIIIa), (VIIIb), (IXa), (IXb) (XIIIa) and (XIIIb) maybe prepared by any of the procedures above for the preparation ofcompounds of formula (I), but wherein R¹¹, R¹⁵ or R²⁶ isC₁₋₄alkoxycarbonyl.

-   Process 7): Compounds of formula (Xa) and (Xb) may be reacted with    thiols of formula (XI) in the presence of base, for Example an    inorganic base such as sodium carbonate or an organic base such as    Hunigs base, in the presence of a suitable solvent such as DMF or    THF at a temperature in the range of 0° C. to reflux.

Compounds of formula (Xa) and (Xb) may be prepared by any of theprocedures above for the preparation of compounds of formula (I), butwherein one of R⁴ and R⁵ is L.

Compounds of formula (XI) are commercially available compounds, or theyare known in the literature, or they are prepared by standard processesknown in the art.

It will be appreciated that certain of the various ring substituents inthe compounds of the present invention may be introduced by standardaromatic substitution reactions or generated by conventional functionalgroup modifications either prior to or immediately following theprocesses mentioned above, and as such are included in the processaspect of the invention. Such reactions and modifications include, forexample, introduction of a substituent by means of an aromaticsubstitution reaction, reduction of substituents, alkylation ofsubstituents and oxidation of substituents. The reagents and reactionconditions for such procedures are well known in the chemical art.Particular examples of aromatic substitution reactions include theintroduction of a nitro group using concentrated nitric acid, theintroduction of an acyl group using, for example, an acyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; the introduction of an alkyl group using an alkyl halide andLewis acid (such as aluminium trichloride) under Friedel Craftsconditions; and the introduction of a halogeno group. Particularexamples of modifications include the reduction of a nitro group to anamino group by for example, catalytic hydrogenation with a nickelcatalyst or treatment with iron in the presence of hydrochloric acidwith heating; oxidation of alkylthio to alkylsulphinyl oralkylsulphonyl.

It will also be appreciated that in some of the reactions mentionedherein it may be necessary/desirable to protect any sensitive groups inthe compounds. The instances where protection is necessary or desirableand suitable methods for protection are known to those skilled in theart. Conventional protecting groups may be used in accordance withstandard practice (for illustration see T. W. Green, Protective Groupsin Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactantsinclude groups such as amino, carboxy or hydroxy it may be desirable toprotect the group in some of the reactions mentioned herein.

A suitable protecting group for an amino or alkylamino group is, forexample, an acyl group, for example an alkanoyl group such as acetyl, analkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl ort-butoxycarbonyl group, an arylmethoxycarbonyl group, for examplebenzyloxycarbonyl, or an aroyl group, for example benzoyl. Thedeprotection conditions for the above protecting groups necessarily varywith the choice of protecting group. Thus, for example, an acyl groupsuch as an alkanoyl or alkoxycarbonyl group or an aroyl group may beremoved for example, by hydrolysis with a suitable base such as analkali metal hydroxide, for example lithium or sodium hydroxide.Alternatively an acyl group such as a t-butoxycarbonyl group may beremoved, for example, by treatment with a suitable acid as hydrochloric,sulphuric or phosphoric acid or trifluoroacetic acid and anarylmethoxycarbonyl group such as a benzyloxycarbonyl group may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon, or by treatment with a Lewis acid for example borontris(trifluoroacetate). A suitable alternative protecting group for aprimary amino group is, for example, a phthaloyl group which may beremoved by treatment with an alkylamine, for exampledimethylaminopropylamine, or with hydrazine.

A suitable protecting group for a hydroxy group is, for example, an acylgroup, for example an alkanoyl group such as acetyl, an aroyl group, forexample benzoyl, or an arylmethyl group, for example benzyl. Thedeprotection conditions for the above protecting groups will necessarilyvary with the choice of protecting group. Thus, for example, an acylgroup such as an alkanoyl or an aroyl group may be removed, for example,by hydrolysis with a suitable base such as an alkali metal hydroxide,for example lithium or sodium hydroxide. Alternatively an arylmethylgroup such as a benzyl group may be removed, for example, byhydrogenation over a catalyst such as palladium-on-carbon.

A suitable protecting group for a carboxy group is, for example, anesterifying group, for example a methyl or an ethyl group which may beremoved, for example, by hydrolysis with a base such as sodiumhydroxide, or for example a t-butyl group which may be removed, forexample, by treatment with an acid, for example an organic acid such astrifluoroacetic acid, or for example a benzyl group which may beremoved, for example, by hydrogenation over a catalyst such aspalladium-on-carbon.

The protecting groups may be removed at any convenient stage in thesynthesis using conventional techniques well known in the chemical art.

As stated hereinbefore the compounds defined in the present inventionpossess IBAT inhibitory activity. These properties may be assessed, forexample, using an in vitro test assay for studying the effect on bileacid uptake in IBAT-transfected cells (Smith L., Price-Jones M. J.,Hugnes K. T. and Jones N. R. A.; J Biomolecular Screening, 3, 227–230)or in vivo by studying the effect on radiolabelled bile acid absorptionin mice/rats (Lewis M. C., Brieaddy L. E. and Root C., J., J Lip Res1995, 36, 1098–1105).

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

The composition may be in a form suitable for oral administration, forexample as a tablet or capsule, for parenteral injection (includingintravenous, subcutaneous, intramuscular, intravascular or infusion) asa sterile solution, suspension or emulsion, for topical administrationas an ointment or cream or for rectal administration as a suppository.

In general the above compositions may be prepared in a conventionalmanner using conventional excipients.

The compound of formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, will normally beadministered to a warm-blooded animal at a unit dose within the range5–5000 mg per square meter body area of the animal, i.e. approximately0.1–100 mg/kg or 0.01–50 mg/kg, and this normally provides atherapeutically-effective dose. A unit dose form such as a tablet orcapsule will usually contain, for example 1–250 mg of active ingredient.Preferably a daily dose in the range of 1–50 mg/kg is employed. Inanother aspect a daily dose in the rage of 0.02–20 mg/kg is employed.However the daily dose will necessarily be varied depending upon thehost treated, the particular route of administration, and the severityof the illness being treated. Accordingly the optimum dosage may bedetermined by the practitioner who is treating any particular patient.

According to a further aspect of the present invention there is provideda compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use in a method of prophylactic or therapeutictreatment of a warm-blooded animal, such as man.

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, are effective IBAT inhibitors, and accordingly havevalue in the treatment of disease states associated with hyperlipidaemicconditions.

Thus according to this aspect of the invention there is provided acompound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore for use as a medicament.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in theproduction of an IBAT inhibitory effect in a warm-blooded animal, suchas man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof hyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof dyslipidemic conditions and disorders such as hyperlipidaemia,hypertrigliceridemia, hyperbetalipoproteinemia (high LDL),hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia,hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia andhypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such asman.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof different clinical conditions such as atherosclerosis,arteriosclerosis, arrhythmia, hyper-thrombotic conditions, vasculardysfunction, endothelial dysfunction, heart failure, coronary heartdiseases, cardiovascular diseases, myocardial infarction, anginapectoris, peripheral vascular diseases, inflammation of cardiovasculartissues such as heart, valves, vasculature, arteries and veins,aneurisms, stenosis, restenosis, vascular plaques, vascular fattystreaks, leukocyte, monocytes and/or macrophage infiltrate, intimitalthickening, medial thinning, infectious and surgical trauma and vascularthrombosis, stroke and transient ischaemic attacks in a warm-bloodedanimal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, as definedhereinbefore in the manufacture of a medicament for use in the treatmentof atherosclerosis, coronary heart diseases, myocardial infarction,angina pectoris, peripheral vascular diseases, stroke and transientischaemic attacks in a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating dyslipidemic conditions and disorders suchas hyperlipidaemia, hypertrigliceridemia, hyperbetalipoproteinemia (highLDL), hyperprebetalipoproteinemia (high VLDL), hyperchylomicronemia,hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia andhypoalphalipoproteinemia (low HDL) in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating different clinical conditions such asatherosclerosis, arteriosclerosis, arrhythmia, hyper-thromboticconditions, vascular dysfunction, endothelial dysfunction, heartfailure, coronary heart diseases, cardiovascular diseases, myocardialinfarction, angina pectoris, peripheral vascular diseases, inflammationof cardiovascular tissues such as heart, valves, vasculature, arteriesand veins, aneurisms, stenosis, restenosis, vascular plaques, vascularfatty streaks, leukocyte, monocytes and/or macrophage infiltrate,intimital thickening, medial thinning, infectious and surgical traumaand vascular thrombosis, stroke and transient ischaemic attacks in needof such treatment which comprises administering to said animal aneffective amount of a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating atherosclerosis, coronary heart diseases,myocardial infarction, angina pectoris, peripheral vascular diseases,stroke and transient ischaemic attacks in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

There is evidence that an IBAT inhibitor might potentially be useful inthe treatment and/or prevention of gallstones. According to a furtherfeature of this aspect of the invention there is provided a method oftreating and/or preventing gallstones in a warm-blooded animal, such asman, in need of such treatment which comprises administering to saidanimal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

The size of the dose required for the therapeutic or prophylactictreatment will necessarily be varied depending on the host treated, theroute of administration and the severity of the illness being treated. Aunit dose in the range, for example, 1–100 mg/kg, preferably 1–50 mg/kgis envisaged.

The IBAT inhibitory activity defined hereinbefore may be applied as asole therapy or may involve, in addition to a compound of the invention,one or more other substances and/or treatments. Such conjoint treatmentmay be achieved by way of the simultaneous, sequential or separateadministration of the individual components of the treatment. Accordingto this aspect of the invention there is provided a pharmaceuticalproduct comprising a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,as defined hereinbefore and an additional IBAT inhibitory substance asdefined hereinbefore and an additional hypolipidaemic agent for theconjoint treatment of hyperlipidaemia.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with an HMG Co-Areductase inhibitor, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable HMG Co-A reductaseinhibitors, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are statins well known in the art.Particular statins are fluvastatin, lovastatin, pravastatin,simvastatin, atorvastatin, cerivastatin, bervastatin, dalvastatin,mevastatin and(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid (rosuvastatin), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. A particular statin isatorvastatin, or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof. A more particular statin isatorvastatin calcium salt. A further particular statin is(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulphonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoicacid (rosuvastatin), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof. A preferable particularstatin is rosuvastatin calcium salt.

In an additional aspect of the invention, the compound of formula (I),or a pharmaceutically acceptable salt, solvate, solvate of such a saltor a prodrug thereof may be administered in association with an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and/or a bile acid binderthereby avoiding a possible risk of excess of bile acids in colon causedby the inhibition of the ileal bile acid transport system. An excess ofbile acids in the visceral contents may cause diarrhoea. Thus, thepresent invention also provides a treatment of a possible side effectsuch as diarrhoea in patients during therapy comprising the compound offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof.

An HMG CoA-reductase inhibitor, or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof will by its actiondecrease the endogenous cholesterol available for the bile acidsynthesis and have an additive effect in combination with the compoundof formula (I), or a pharmaceutically acceptable salt, solvate, solvateof such a salt or a prodrug thereof on lipid lowering.

Suitable bile acid binders for such a combination therapy are resins,such as cholestyramine and cholestipol. One advantage is that the doseof bile acid binder might be kept lower than the therapeutic dose fortreatment of cholesterolaemia in single treatment comprising solely abile acid binder. By a low dose of bile acid binder any possible sideeffects caused by poor tolerance of the patient to the therapeutic dosecould also be avoided.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a bile acid binder.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in simultaneous, sequential or separate administrationwith a bile acid binder.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula a), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder, in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a bile acid binder in association with apharmaceutically acceptable diluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a bile acid binder.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and an HMG Co-A reductase inhibitor, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof and a bileacid binder.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) a bile acid binder; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof; in a    second unit dosage form;-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a bile acid binder, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable    salt, solvate, solvate of such a salt or a prodrug thereof, in a    second unit dosage form; and-   c) a bile acid binder; in a third unit dosage form; and-   d) container means for containing said first, second and third    dosage forms.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the production of an IBAT inhibitory effect in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and a bile acidbinder, in the manufacture of a medicament for use in the production ofan IBAT inhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, and an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the production of an IBATinhibitory effect in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a bile acidbinder, in the manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, an HMG Co-Areductase inhibitor, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, and a bile acid binder, inthe manufacture of a medicament for use in the treatment ofhyperlipidaemic conditions in a warm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of an HMG Co-A reductase inhibitor, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptableexcipient, with the simultaneous, sequential or separate administrationof an effective amount of a bile acid binder, optionally together with apharmaceutically acceptable diluent or carrier to a warm-blooded animal,such as man in need of such therapeutic treatment.

According to an additional further aspect of the present invention thereis provided a combination treatment comprising the administration of aneffective amount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administrationone or more of the following agents selected from:

-   -   a CETP (cholesteryl ester transfer protein) inhibitor, for        example those referenced and described in WO 00/38725 page 7        line 22-page 10, line 17 which are incorporated herein by        reference;    -   a cholesterol absorption antagonist for example azetidinones        such as SCH 58235 and those described in U.S. Pat. No. 5,767,115        which are incorporated herein by reference;    -   a MTP (microsomal transfer protein) inhibitor for example those        described in Science, 282, 751–54, 1998 which are incorporated        herein by reference;    -   a fibric acid derivative; for example clofibrate, gemfibrozil,        fenofibrate, ciprofibrate and bezafibrate;    -   a nicotinic acid derivative, for example, nicotinic acid        (niacin), acipimox and niceritrol;    -   a phytosterol compound for example stanols;    -   probucol;    -   an anti-obesity compound for example orlistat (EP 129,748) and        sibutramine (GB 2,184,122 and U.S. Pat. No. 4,929,629);    -   an antihypertensive compound for example an angiotensin        converting enzyme (ACE) inhibitor, an angiotensin II receptor        antagonist, an andrenergic blocker, an alpha andrenergic        blocker, a beta andrenergic blocker, a mixed alpha/beta        andrenergic blocker, an andrenergic stimulant, calcium channel        blocker, a diuretic or a vasodilator;    -   insulin;    -   sulphonylureas including glibenclamide, tolbutamide;    -   metformin; and/or    -   acarbose;        or a pharmaceutically acceptable salt, solvate, solvate of such        a salt or a prodrug thereof, optionally together with a        pharmaceutically acceptable diluent or carrier to a warm-blooded        animal, such as man in need of such therapeutic treatment.

Particular ACE inhibitors or pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof, including activemetabolites, which can be used in combination with a compound of formula(I) include but are not limited to, the following compounds: alacepril,alatriopril, altiopril calcium, ancovenin, benazepril, benazeprilhydrochloride, benazeprilat, benzoylcaptopril, captopril,captopril-cysteine, captopril-glutathione, ceranapril, ceranopril,ceronapril, cilazapril, cilazaprilat, delapril, delapril-diacid,enalapril, enalaprilat, enapril, epicaptopril, foroxymithine,fosfenopril, fosenopril, fosenopril sodium, fosinopril, fosinoprilsodium, fosinoprilat, fosinoprilic acid, glycopril, hemorphin-4,idrapril, imidapril, indolapril, indolaprilat, libenzapril, lisinopril,lyciumin A, lyciumin B, mixanpril, moexipril, moexiprilat, moveltipril,muracein A, muracein B, muracein C, pentopril, perindopril,perindoprilat, pivalopril, pivopril, quinapril, quinapril hydrochloride,quinaprilat, ramipril, ramiprilat, spirapril, spirapril hydrochloride,spiraprilat, spiropril, spiropril hydrochloride, temocapril, temocaprilhydrochloride, teprotide, trandolapril, trandolaprilat, utibapril,zabicipril, zabiciprilat, zofenopril and zofenoprilat. Preferred ACEinhibitors for use in the present invention are ramipril, ramiprilat,lisinopril, enalapril and enalaprilat. More preferred ACE inhibitors foruses in the present invention are ramipril and ramiprilat.

Preferred angiotensin II antagonists, pharmaceutically acceptable salts,solvates, solvate of such salts or a prodrugs thereof for use incombination with a compound of formula (I) include, but are not limitedto, compounds: candesartan, candesartan cilexetil, losartan, valsartan,irbesartan, tasosartan, telmisartan and eprosartan. Particularlypreferred angiotensin II antagonists or pharmaceutically acceptablederivatives thereof for use in the present invention are candesartan andcandesartan cilexetil.

In another aspect of the invention, the compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, may be administered in association with a PPAR alphaand/or gamma agonist, or pharmaceutically acceptable salts, solvates,solvates of such salts or prodrugs thereof. Suitable PPAR alpha and/orgamma agonists, pharmaceutically acceptable salts, solvates, solvates ofsuch salts or prodrugs thereof are well known in the art. These includethe compounds described in WO 01/12187, WO 01/12612, WO 99/62870, WO99/62872, WO 99/62871, WO 98/57941, WO 01/40170, J Med Chem, 1996, 39,665, Expert Opinion on Therapeutic Patents, 10 (5), 623–634 (inparticular the compounds described in the patent applications listed onpage 634) and J Med Chem, 2000, 43, 527 which are all incorporatedherein by reference. Particularly a PPAR alpha and/or gamma agonistrefers to WY-14643, clofibrate, fenofibrate, bezafibrate, GW 9578,troglitazone, pioglitazone, rosiglitazone, eglitazone, proglitazone,BRL-49634, KRP-297, JTT-501, SB 213068, GW 1929, GW 7845, GW 0207,L-796449, L-165041 and GW 2433. Particularly a PPAR alpha and/or gammaagonist refers to(S)-2-ethoxy-3-[4-(2-{4-methanesulphonyloxyphenyl}ethoxy)phenyl]propanoic acid and pharmaceutically acceptable salts thereof.

Therefore in an additional feature of the invention, there is provided amethod for producing an IBAT inhibitory effect in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore in an additional feature of the invention, there is provided amethod of treating hyperlipidemic conditions in a warm-blooded animal,such as man, in need of such treatment which comprises administering tosaid animal an effective amount of a compound of formula (I), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof in simultaneous, sequential or separate administrationwith an effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further aspect of the invention there is provided apharmaceutical composition which comprises a compound of formula (I), ora pharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, and a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, in association with a pharmaceutically acceptablediluent or carrier.

According to a further aspect of the present invention there is provideda kit comprising a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,and a PPAR alpha and/or gamma agonist, or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof. According toa further aspect of the present invention there is provided a kitcomprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, in a first    unit dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof; in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.

According to a further aspect of the present invention there is provideda kit comprising:

-   a) a compound of formula (I), or a pharmaceutically acceptable salt,    solvate, solvate of such a salt or a prodrug thereof, together with    a pharmaceutically acceptable diluent or carrier, in a first unit    dosage form;-   b) a PPAR alpha and/or gamma agonist, or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof, in a second unit dosage form; and-   c) container means for containing said first and second dosage    forms.    According to another feature of the invention there is provided the    use of a compound of the formula (I), or a pharmaceutically    acceptable salt, solvate, solvate of such a salt or a prodrug    thereof, and a PPAR alpha and/or gamma agonist, or a    pharmaceutically acceptable salt, solvate, solvate of such a salt or    a prodrug thereof, in the manufacture of a medicament for use in the    production of an IBAT inhibitory effect in a warm-blooded animal,    such as man.

According to another feature of the invention there is provided the useof a compound of the formula (I), or a pharmaceutically acceptable salt,solvate, solvate of such a salt or a prodrug thereof, a PPAR alphaand/or gamma agonist, or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, in the manufacture of amedicament for use in the treatment of hyperlipidaemic conditions in awarm-blooded animal, such as man.

According to a further aspect of the present invention there is provideda combination treatment comprising the administration of an effectiveamount of a compound of the formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt or a prodrug thereof,optionally together with a pharmaceutically acceptable diluent orcarrier, with the simultaneous, sequential or separate administration ofan effective amount of a PPAR alpha and/or gamma agonist, or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, optionally together with a pharmaceutically acceptablediluent or carrier to a warm-blooded animal, such as man in need of suchtherapeutic treatment.

In addition to their use in therapeutic medicine, the compounds offormula (I), or a pharmaceutically acceptable salt, solvate, solvate ofsuch a salt or a prodrug thereof, are also useful as pharmacologicaltools in the development and standardisation of in vitro and in vivotest systems for the evaluation of the effects of inhibitors of IBAT inlaboratory animals such as cats, dogs, rabbits, monkeys, rats and mice,as part of the search for new therapeutic agents.

Many of the intermediates described herein are novel and are thusprovided as a further feature of the invention. For example compounds offormula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) and (XIIIb) show IBATinhibitory activity when tested in the above referenced in vitro testassay and are thus claimed as a further feature of the invention.

Thus in a further feature of the invention, there is provided a compoundof formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

Therefore according to a further aspect of the invention there isprovided a pharmaceutical composition which comprises a compound offormula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof, as defined hereinbefore in association with apharmaceutically-acceptable diluent or carrier.

According to an additional aspect of the present invention there isprovided a compound of the formula (VIIIa), (VIIIb), (IXa), (IXb),(XIIIa) or (XIIIb), or a pharmaceutically acceptable salt, solvate,solvate of such a salt or a prodrug thereof, as defined hereinbefore foruse in a method of prophylactic or therapeutic treatment of awarm-blooded animal, such as man.

Thus according to this aspect of the invention there is provided acompound of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or(XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof, as defined hereinbefore for use as amedicament.

According to another feature of the invention there is provided the useof a compound of the formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or(XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof as defined hereinbefore in the manufactureof a medicament for use in the production of an IBAT inhibitory effectin a warm-blooded animal, such as man.

According to another feature of the invention there is provided the useof a compound of the formula (VIIIa), (VIIIb),(IXa), (IXb), (XIIIa) or(XIIIb), or a pharmaceutically acceptable salt, solvate, solvate of sucha salt or a prodrug thereof as defined hereinbefore in the manufactureof a medicament for use in the treatment of hyperlipidaemic conditionsin a warm-blooded animal, such as man.

According to a further feature of this aspect of the invention there isprovided a method for producing an IBAT inhibitory effect in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

According to a further feature of this aspect of the invention there isprovided a method of treating hyperlipidemic conditions in awarm-blooded animal, such as man, in need of such treatment whichcomprises administering to said animal an effective amount of a compoundof formula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb), or apharmaceutically acceptable salt, solvate, solvate of such a salt or aprodrug thereof.

In the above other pharmaceutical composition, process, method, use andmedicament manufacture features, the alternative and preferredembodiments of the compounds of the invention described herein alsoapply.

EXAMPLES

The invention will now be illustrated in the following non limitingExamples, in which standard techniques known to the skilled chemist andtechniques analogous to those described in these Examples may be usedwhere appropriate, and in which, unless otherwise stated:

-   (i) evaporations were carried out by rotary evaporation in vacuo and    work up procedures were carried out after removal of residual solids    such as drying agents by filtration;-   (ii) all reactions were carried out under an inert atmosphere at    ambient temperature, typically in the range 18–25° C., with solvents    of HPLC grade under anhydrous conditions, unless otherwise stated;-   (iii) column chromatography (by the flash procedure) was performed    on Silica gel 40–63 μm (Merck);-   (iv) yields are given for illustration only and are not necessarily    the maximum attainable;-   (v) the structures of the end products of the formula (I) were    generally confirmed by nuclear (generally proton) magnetic resonance    (NMR) and mass spectral techniques; magnetic resonance chemical    shift values were measured in deuterated CDCl₃ (unless otherwise    stated) on the delta scale (ppm downfield from tetramethylsilane);    proton data is quoted unless otherwise stated; spectra were recorded    on a Varian Mercury-300 MHz, Varian Unity plus-400 MHz, Varian Unity    plus-600 MHz or on Varian Inova-500 MHz spectrometer unless    otherwise stated data was recorded at 400 MHz; and peak    multiplicities are shown as follows: s, singlet; d, doublet; dd,    double doublet; t, triplet; tt, triple triplet; q, quartet; tq,    triple quartet; m, multiplet; br, broad; ABq, AB quartet; ABd, AB    doublet, ABdd, AB doublet of doublets; dABq, doublet of AB quartets;    LCMS were recorded on a Waters ZMD, LC column xTerra MS C₈(Waters),    detection with a BP 1100 MS-detector diode array equipped; mass    spectra (MS) (loop) were recorded on VG Platform II (Fisons    Instruments) with a HP-1100 MS-detector diode array equipped; unless    otherwise stated the mass ion quoted is (MH⁺); unless further    details are specified in the text, analytical high performance    liquid chromatography (HPLC) was performed on Prep LC 2000 (Waters),    Cromasil C₇, 7 μm, (Akzo Nobel); MeCN and de-ionised water 10 mM    ammonium acetate as mobile phases, with suitable composition;-   (vii) intermediates were not generally fully characterised and    purity was assessed by thin layer chromatography (TLC), HPLC,    infra-red (IR), MS or NMR analysis;-   (viii) where solutions were dried sodium sulphate was the drying    agent;-   (ix) where an “ISOLUTE” column is referred to, this means a column    containing 2 g of silica, the silica being contained in a 6 ml    disposable syringe and supported by a porous disc of 54 Å pore size,    obtained from International Sorbent Technology under the name    “ISOLUTE”; “ISOLUTE” is a registered trade mark;-   (x) the following abbreviations may be used hereinbefore or    hereinafter:

DCM dichloromethane; DMF N,N-dimethylformamide; TBTUo-Benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate;EtOAc EtOAC; MeCN acetonitrile; TFA trifluoroacetic acid; IPAisopropanol; DIPEA di-isopropylethylamine; and THF tetrahydrofuran.

Example 11,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N—((R)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 29; 300 mg, 0.46 mmol) was dissolved in methanol (5 ml). NaOH(100 mg in 0.2 ml water) was added to the solution and the mixture wasstirred at room temperature for 1 hour. Acetic acid (0.3 ml) was added.The solvent was evaporated under reduced pressure and the residue wasextracted with DCM/water. The DCM layer was separated, dried andevaporated under reduced pressure to give the title compound 270 mg(92%). NMR, 500 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.1 (s, 3H) 3.2(brs, 2H), 3.6–3.8 (m, 2H), 4.6 (s, 2H), 5.6 (d, 1H), 6.6 (s, 1H),6.9–7.5 (m, 11H), 7.8 (d, 1H).

Examples 2–9

The following compounds were synthesised by the procedure of Example 1using the appropriate starting material.

Ex Compound NMR SM 2

(300MHz, CD₃OD) 0.9–0.95(m, 6H), 1.05–1.3(m, 8H), 1.4–1.6(m, 4H), 2.2(s,3H), 3.25(s,2H), 3.75(brs, 2H), 4.65(dd,2H), 5.2(s, 1H), 6.7–7.3(m,10H),7.4(s, 1H) Meth30 3

(300MHz, CD₃OD) 0.75–0.85(m, 6H), 1.0–1.6(m, 12H), 2.2(s, 3H), 3.75(brs,2H), 3.25(s,2H), 4.6–4.7(m, 2H), 5.7(s,1H), 6.7(s, 1H), 6.9–7.3(m,8H),7.4(s, 1H) Meth31 4

(300MHz, CD₃OD) 0.75–0.9(m, 6H), 1.0–1.6(m, 12H), 2.2(s, 3H), 3.25(s,2H), 3.75(brs,2H), 4.6–4.8(m, 2H), 5.45(s,1H), 6.7(s, 1H),6.95–7.3(m,5H), 7.4(s, 1H), 7.6(s, 4H) Meth32 5

(500MHz) 0.7–0.8(m, 6H), 1.0–1.6(m, 12H), 3.2(brs, 2H), 3.6(brs, 2H),4.48(m, 2H), 5.0(s,1H), 6.5(d, 1H), 6.7–7.4(m,10H), 7.9(s, 1H) Meth39 6

(DMSO-d₆) 0.7–0.8(m, 6H),0.9–1.6(m, 12H), 3.2(brs, 2H),3.7(brs, 2H),4.6–4.8(m, 3H),6.6(d, 2H), 6.9–7.3(m, 8H), 7.4(s, 1H), 8.3(d, 1H) Meth407

M/z = 768.9 Meth67 8¹

(300MHz, CD₃OD) 0.75–0.9(m, 6H), 1.0–1.25(m, 4H), 1.4–1.6(m, 4H),2.15(s, 3H), 3.1–3.3(m, 4H), 3.5–3.8(m, 5H),4.75(ABq, 2H), 5.45(s,2H),6.75(s, 1H), 6.95–7.5(11H);m/z 711.3 Meth42 9

(500MHz, DMSO-d₆) 0.7–0.8(m, 6H), 0.9–1.6(m, 12H), 2.2(s, 3H) 3.2–3.8(m,8H), 4.8(ABq, 2H), 5.6(d, 1H), 6.7(s,1H), 6.8–7.5(m, 11H), 7.8(brs,1H),8.6(d, 1H), 8.8(t, 1H) Meth69 ¹Ethanol instead of methanol, purified bypreparative HPLC using MeCN and ammonium acetate buffer(55:45) as eluent

Example 101,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{1-[N—((R)-1′-phenyl-1′-carboxymethyl)carbamoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{1-[N—((R)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 33; 103 mg, 0.15 mmol) was dissolved in a mixture of THF and H₂O(2:1, 3 ml). LiOH (7 mg, 0.3 mmol) was added and the mixture was stirredfor 7 hours at ambient temperature. Most of the solvent was removedunder reduced pressure and the crude product was purified by preparativeHPLC using MeCN and ammonium acetate buffer (45:55) as eluent to givethe title compound 97 mg (96%). NMR (DMSO-d₆) 0.60–0.80 (m, 6H),0.90–1.60 (m, 11H), 3.15–3.45 (m, 2H), 3.50–3.90 (m, 2H), 4.95–5.25 (m,2H), 6.85–7.55 (m, 12H), 8.55–8.95 (m, 1H).

Examples 11–16

The following compounds were synthesised by the procedure of Example 10using the appropriate starting material.

Ex Compound NMR SM 11

((CD₃)₂CO) 0.70–0.90(m, 6H),0.95–1.35(m, 4H), 1.40–1.75(m,4H),3.15–3.35(m, 2H), 3.80(brs,2H), 5.40(d, 1H), 5.90–6.15(2s,1H),6.95–7.75(m, 18H) Meth34 12

(CD₃OD) 0.75–0.85(m, 6H), 1.00–1.30(m, 8H), 1.35–1.55(m, 4H),3.20(s,2H), 3.60(s, 3H), 3.75(brs,2H), 4.60(ABq, 2H), 5.40(s, 1H),6.50(s, 1H),6.95–7.45(m, 10H),7.55(s, 1H) Meth35 13

(CD₃OD) 0.75–0.85(m, 6H), 1.00–1.30(m, 8H), 1.35–1.55(m, 4H),3.20(s,2H), 3.55(s, 3H), 3.75(brs,2H), 3.90(ABq, 2H), 4.60(ABq,2H), 5.60(s,1H), 6.50(s, 1H),6.95–7.45(m, 10H), 7.55(s, 1H) Meth36 14

(CD₃OD) 0.75–0.85(m, 6H), 1.00–1.30(m, 8H), 1.35–1.60(m, 4H),3.20(s,2H), 3.60(s, 3H), 3.75(brs,2H), 4.55(ABq, 2H), 5.55(s, 1H),6.50(s, 1H),6.95–7.45(m, 9H),7.50(s, 1H) Meth37 15

(CD₃OD) 0.75–0.85(m, 6H), 1.00–1.30(m, 8H), 1.35–1.60(m, 4H),2.15(s,3H), 3.25(s, 2H), 3.75(brs,2H), 4.65(ABq, 2H), 5.60(s, 1H),6.70(s, 1H),6.90–7.45(m, 10H) Meth38 16

(CD₃OD) 7.55–7.41(3H, m), 7.35–7.20(5H, m), 7.15–7.08(3H,m),7.04–6.98(1H, m), 5.48–5.32(1H,m), 4.80–4.60(2H, m), 4.00–3.56(4H,m), 3.27–3.22(2H, m), 1.61–1.00(11H, m), 0.83–0.74(6H, m) Meth70

Example 171,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 46; 60 mg, 0.091 mmol) was dissolved in THF (1 ml) and added toa solution of lithium hydroxide monohydrate (12.6 mg, 0.29 mmol) inwater (1 ml). The mixture was stirred occasionally for 30 minutes. 2MHCl solution (0.3 ml) was added and the water layer was extracted withDCM. The organic layer was washed once with brine, dried, filtered andevaporated at reduced pressure to give the title compound 48 mg (82%).NMR (CD₃OD) 0.73–0.84 (m, 6H), 1.0–1.6 (m, 8H), 3.27 (brs, 2H),3.60–3.90 (m, 2H), 4.71 (ABq, 2H), 5.47–5.55 (m, 1H), 7.02 (brt, 1H),7.08–7.17 (m, 3H), 7.25–7.46 (m, 7H), 7.52 (s, 1H), 8.43 (d, NH); m/z643.5.

Examples 18–21

The following compounds were synthesised by the procedure of Example 17using the appropriate starting material.

Ex Compound NMR or m/z SM 18¹

M/z 670(M + NH₄ ⁺) Meth43 19²

(CD₃OD) 0.70–0.90(m, 6H), 1.0–1.32(m, 4H), 1.32–1.70(m, 4H),2.15(s, 3H),2.85(brs, 3H), 3.23(brs, 2H), 3.53–3.93(m, 2H), 4.99(ABq, 2H), 6.27(s,1H), 6.71(s,1H), 6.94(t, 1H), 7.07(d, 2H), 7.25(t, 2H), 7.3–7.47(m, 6H);m/z 625.3 Meth62 20

(CD₃OD) 0.75–0.84(m, 6H), 1.0–1.29(m, 4H), 1.36–1.65(m, 4H),2.15(s, 3H),2.82–2.97(m, 2H),3.22(brs, 2H), 3.6–3.85(m, 2H),4.66(ABq, 2H), 5.43(t,1H), 6.71(s, 1H), 6.96(t, 1H), 7.09(d, 2H),7.2–7.38(m, 7H), 7.40(s, 1H);m/z625.4 Meth112 21

(600MHz, CD₃OD) 0.77–0.88(m,6H), 1.0–1.32(m, 4H), 1.39–1.70(m, 4H),2.16(s, 3H), 2.88(brs,3H), 3.25(brs, 2H), 3.52–3.93(m,2H), 5.03(ABq,2H), 6.28(s, 1H),6.73(s, 1H), 6.96(t, 1H), 7.09(brd,2H), 7.27(t, 2H),7.32–7.46(m,6H) Meth79 ¹2.2 equivalents of LiOH in THF/water (4/1)²Purified by preparative HPLC using an MeCN/ammonium acetate buffergradient(5/95 to 100/0) as eluent

Example 221,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesised from1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 61) by the procedure of Example 17, except that the water layerwas extracted with EtOAc. The product was purified by preparative HPLCusing an MeCN/ammonium acetate buffer gradient (5/95 to 100/0) aseluent. NMR 0.75–0.83 (m, 6H), 1.0–1.25 (m, 4H), 1.32–1:52 (m, 3H),1.55–1.70 (m, 1H), 3.20 (ABq, 2H), 3.65–3.83 (m, 2H), 4.62 (ABq, 2H),5.68 (d, 1H), 7.04–7.15 (m, 4H), 7.3–7.5 (m, 8H), 7.87 (brd, 1H); m/z643.1.

Example 231,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(N-{(S)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineammonium salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 17; 48 mg, 0.075 mmol) and 2-aminoethanesulphonic acid (17 mg,0.14 mmol) was dissolved in DMF (2 ml) and DIPEA (0.052 ml, 0.30 mmol).The mixture was stirred for 15 min at 60° C. TBTU (31 mg, 0.097 mmol)was added and the mixture was stirred for 2 hours at 60° C. The solventwas evaporated at reduced pressure. The residue was purified bypreparative HPLC using an MeCN/ammonium acetate buffer gradient (5/95 to100/0) as eluent. Lyophilisation gave the title compound 4 mg (7%). NMR(CD₃OD) 0.75–0.83 (m, 6H), 0.95–1.65 (m, 8H), 2.85–3.0 (m, 2H), 3.27(brs, 2H), 3.5–3.9 (m, 4H), 4.72 (ABq, 2H), 5.48 (s, 1H), 7.02 (brt,1H), 7.09–7.15 (m, 3H), 7.25–7.52 (m, 8H); m/z 750.3.

Examples 24–37

The following compounds were prepared by the same procedure. The acid (1equiv) was dissolved in THF (1 ml) and added to a solution of lithiumhydroxide monohydrate (12.6 mg, 2.9–6.6 equiv) in water (1 ml). Themixture was stirred occasionally and after 1.5–6 hours the deprotectionwas completed (according to LC-MS). 2M HCl-solution (0.3 ml) was added.

Examples 24–33

The reaction mixture was put on a syringe filled with hydramatrix®. Theproduct was eluted with DCM. The DCM was dried, filtered and evaporatedat reduced pressure. The product was purified by preparative HPLC usingan MeCN/ammonium acetate buffer gradient (5/95 to 100/0) as eluent.

Examples 34–37

The water layer was extracted two times with DCM. The organic layer wasdried, filtered and evaporated at reduced pressure.

Ex Compound NMR(CD₃OD) m/z SM 24

0.75–0.84(m, 6H), 1.0–1.25(m,4H), 1.37–1.65(m, 4H), 3.20(brs, 2H),3.55–3.90(m, 5H),4.58(ABq, 2H), 5.33(s, 1H),6.51(s, 1H), 6.97(brt, 1H),7.12(brd, 2H), 7.2–7.33(m, 5H), 7.41(brd, 2H), 7.54(s, 1H) 595.4 Meth4725

0.73–0.85(m, 6H), 1.0–1.3(m,4H), 1.35–1.65(m, 4H), 2.17(s,3H), 3.23(brs,2H), 3.55–3.90(m, 2H), 4.71(ABq, 2H), 5.49–5.52(m, 1H), 6.73(s, 1H),6.96(brt, 1H), 7.10(brd, 2H), 7.23–7.45(m, 8H), 8.36(brd, NH) 611.2Meth48 26

0.74–0.84(m, 6H), 1.0–1.3(m,8H), 1.37–1.54(m, 4H), 3.28(brs, 2H),3.65–3.85(m, 2H),4.72(ABq, 2H), 5.49–5.52(m,1H), 7.04(brt, 1H),7.09–7.18(m, 3H), 7.28–7.46(m, 7H), 7.52(s, 1H), 8.45(brd, NH) 671.2Meth49 27

0.74–0.84(m, 6H), 1.0–1.3(m,4H), 1.35–1.65(m, 4H), 3.21(brs, 2H),3.59(s, 3H), 3.62–3.90(m, 2H), 4.62(ABq, 2H), 5.49(s, 1H), 6.50(s, 1H)6.98(brt,1H), 7.12(brd, 2H), 7.24–7.43(m, 7H), 7.54(s, 1H) 595.3 Meth5028

0.74–0.85(m, 6H), 0.85–1.65(m,14H), 3.21(brs, 2H), 3.6–3.9(m,2H),4.25–4.36(m, 1H), 4.53–4.66(m, 2H), 5.49(s, 1H), 6.47(s, 1H) 6.91–7.0(m,1H), 7.04–7.16(m, 2H), 7.22–7.46(m, 7H),7.51(s, 1H) 623.3 Meth51 29

0.73–0.85(m, 6H), 0.85–1.65(m,8H), 3.24(brs, 3H), 3.34(brs,2H),3.6–3.95(m, 2H), 4.8–4.95(m, 2H), 5.52(s, 1H), 7.06(brt,1H), 7.17(brd,2H), 7.27–7.40(m, 5H), 7.40–7.50(m, 3H), 7.69(s, 1H) 643.3 Meth52 30

0.74–0.84(m, 6H), 0.85–1.55(m,12H), 3.24–3.33(m, 2H), 3.65–3.85(m, 2H),4.65–4.78(m, 2H),5.50(brs, 1H), 6.99–7.2(m, 4H),7.25–7.48(m, 7H),7.51(s, 1H) 671.2 Meth53 31

0.72–0.84(m, 6H), 0.85–1.65(m,8H), 3.27(brs, 2H), 3.54–3.9(m,2H),4.70(ABq, 2H), 5.70(s,1H), 6.63–6.69(m, 1H), 6.71–6.77(m, 2H), 7.02(brt,1H),7.08–7.17(m, 3H), 7.30(brt,2H), 7.52(s, 1H) 675.4 Meth54 32

0.72–0.84(m, 6H), 0.98–1.67(m,8H), 3.21(brs, 2H), 3.54–3.9(m,5H),4.62(ABq, 2H), 5.57(s,1H), 6.51(s, 1H), 6.59–6.73(m,3H), 6.97(brt, 1H,7.12(brd,2H), 7.28(brt, 2H), 7.56(s, 1H) 627.5 Meth55 33

0.73–0. 86(m, 6H), 1.0–1.68(m,8H), 2.19(s, 3H), 3.24(brs,2H),3.55–3.9(m, 2H), 4.71(ABq,2H), 5.53(s, 1H), 6.60–6.73(m,3H), 6.75(s,1H), 6.96(brt, 1H),7.10(brd, 2H), 7.27(brt, 2H),7.44(s, 1H) 643.4 Meth5634

0.74–0.86(m, 6H), 1.0–1.3(m,8H), 1.35–1.57(m, 4H), 2.19(s,3H), 3.23(brs,2H), 3.62–3.85(m, 2H), 4.65(ABq, 2H), 5.28(s, 1H), 6.72(s, 1H),6.94–7.05(m, 3H), 7.12(brd, 2H), 7.28(brt, 2H), 7.39(s, 1H), 7.43(dd,2H)657.3 Meth57 35

0.75–0.86(m, 6H), 1.0–1.3(m,8H), 1.35–1.55(m, 4H), 2.01(s,3H),3.11–3.26(ABq, 2H), 3.6–3.8(m, 2H), 4.58(d, 1H), 4.70(d, 1H), 5.64(s,1H), 6.62(s,1H), 6.91–7.0(m, 2H), 7.01–7.12(m, 3H), 7.23–7.33(m, 4H),7.37(s, 1H), 7.69(brd, 1H) 678.4 Meth58 36

0.76–0.84(m, 6H), 1.0–1.3(m,8H), 1.36–1.53(m, 4H), 3.21(brs, 2H),3.64(s, 3H), 3.67–3.87(m, 2H), 4.57(ABq, 2H), 5.31(s, 1H), 6.50(s, 1H),6.95–7.06(m, 3H), 7.14(brd, 2H), 7.28(brt, 2H), 7.38–7.46(m, 2H),7.51(s,1H) 641.4 Meth59 37

0.75–0.87(m, 6H), 1.0–1.3(m,8H), 1.34–1.53(m, 4H), 3.18(ABq, 2H),3.27(s, 3H), 3.65–3.85(m, 2H), 4.52(d, 1H), 4.65(d, 1H), 5.66(s, 1H),6.30(s,1H), 6.90–7.02(m, 2H), 7.03–7.16(m, 3H), 7.23–7.34(m, 4H),7.50(s,1H), 7.59(brd, 1H) 662.4 Meth60

Example 381,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 22; 50 mg, 0.078 mmol) was dissolved in DMF (1.5 ml). Sodiummethanethiolate (20 mg, 0.29 mmol) was added and the mixture was stirredfor 1.5 hours at 50° C. Acetic acid (40 mg) was added and the solventwas evaporated under reduced pressure. The residue was purified bypreparative HPLC using MeCN/ammonium acetate buffer (45:55) as eluent togive the title compound 29 mg (61%). NMR (DMSO-d₆): 0.7–0.8 (m, 6H),0.9–1.6 (m, 8H), 2.2 (s, 3H), 3.1–3.7 (m, 4H), 4.6–4.8 (m, 3H), 6.7 (s,1H), 6.8–7.4 (m, 11H), 8.3 (d, 1H).

Example 391,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 22; 50 mg, 0.078 mmol), ethanethiol (99 mg, 1.59 mmol) andcaesium carbonate (253 mg, 0.78 mmol) were added to DMF (5 ml) and themixture was stirred for 30 h at 44° C. The solvent was filtered,evaporated under reduced pressure. The residue was purified bypreparative HPLC using MeCN/ammonium acetate buffer (45:55) as eluent.The residue was purified by column chromatography using DCM methanol(100:15) to give the title compound 15 mg (31%). NMR (300 MHz, CD₃OD)0.7–0.85 (m, 6H), 1.0–1.6 (m, 11H), 2.65 (q, 2H), 3.2 (s, 2H), 3.7 (brs,2H), 4.6 (q, 2H), 5.3 (s, 1H), 6.75 (s, 1H), 6.9–7.5 (m, 11H).

Example 401,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(2-hydroxyethylthio)-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 22; 50 mg, 0.078 mmol), 2-mercaptoethanol (281 mg, 3.59 mmol)and caesium carbonate (228 mg, 0.7 mmol) were added to DMF (5 ml) andthe mixture was stirred for 9 hours at 70° C. The solvent was evaporatedunder reduced pressure. The residue was purified by preparative HPLCusing MeCN/ammonium acetate buffer (45:55) as eluent. The collectedfractions were lyophilised to give the title compound 20 mg (40%). NMR(300 MHz, CD₃OD) 0.75–0.85 (m, 6H), 1.0–1.6 (m, 8H), 2.9 (t, 2H), 3.2(s, 2H), 3.55 (t, 2H), 3.7 (brs, 2H), 4.65 (q, 2H), 5.3 (s, 1H), 6.9 (s,1H), 6.95–7.5 (m, 11H).

Example 411,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(2-N′,N′-dimethylaminoethylthio)-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 22; 50 mg, 0.078 mmol), dimethylaminoethanethiol hydrochloride(99 mg, 0.94 mmol), potassium carbonate (129 mg, 0.94 mmol), DIPEA (100mg, 0.77 mmol) and sodium borohydride (35 mg, 0.93 mmol) were added toDMF (10 ml) and the mixture was stirred for 24 hours at 85° C. Thesolvent was filtered and evaporated under reduced pressure. The residuewas purified twice by preparative HPLC using MeCN/ammonium acetatebuffer (40:60) as eluent. The collected fractions were lyophilised togive the title compound. 15 mg (30%). NMR (300 MHz, CD₃OD) 0.75–0.85 (m,6H), 1.0–1.65 (m, 8H), 2.65 (s, 6H), 3.05 (t, 2H), 3.2 (t, 2H), 3.3 (s,2H), 3.75 (brs, 2H), 4.75 (s, 2H), 5.2 (s, 1H), 6.95–7.4 (m, 11), 7.5(s, 1H).

Example 421,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 22; 50 mg, 0.078 mmol), 2-propanethiol (126 mg, 1.65 mmol),caesium carbonate (152 mg, 0.47 mmol), sodium borohydride (25 mg, 0.66mmol) were added to DMF (5 ml) and the mixture was stirred for 5 min at100° C. The solvent was evaporated under reduced pressure. The residuewas purified by preparative HPLC using MeCN/ammonium acetate buffer(45:55) as eluent. The collected fractions were lyophilised to give thetitle compound 15 mg (30%). NMR (300 MHz, DMSO-d₆) 0.7–0.85 (m, 6H),0.95–1.65 (m, 14H), 3.3 (s, 2H), 3.7 (brs, 2H), 4.75 (dd, 2H), 5.05(brs, 1H), 6.75–7.4 (m, 12H), 8.5 (brs, 1H).

Example 431,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(t-butoxycarbonylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 63; 120 mg, 0.17 mmol) was dissolved in DCM (2 ml). TFA (0.7 ml)was added and the mixture was stirred at room temperature for 3 h. Thereaction mixture was evaporated under reduced pressure. The residue waspurified by preparative HPLC using MeCN/ammonium acetate buffer (50:50)as eluent to give the title compound 95 mg (85%). NMR (300 MHz, DMSO-d₆)0.7–0.8 (m, 6H), 0.9–1.6 (m, 12H), 2.2 (s, 3H) 3.2–3.3 (m, 2H), 3.5–3.8(m, 4H), 4.8 (ABq, 2H), 5.6 (d; 1H), 6.7 (s, 1H), 6.8–7.5 (m, 11H),8.5–8.7 (m, 2H).

Examples 44–49

The following compounds were synthesised by the procedure of Example 43using the appropriate starting material.

Ex Compound NMR or m/z SM 44

(300MHz) 0.7–0.9(m, 6H), 1.0–1.7(m, 8H), 3.2(m, 2H), 3.75(brs,2H),3.9–4.0(m, 1H), 4.15–4.25(m,1H), 4.5–4.7(m, 2H), 5.75–5.9(m,1H),7.05–7.2(m, 4H), 7.25–7.4(m, 5H), 7.45–7.55(m, 3H), 8.2(d,1H) Meth64 45

(CD₃OD) 0.70–0.90(m, 6H), 1.00–1.30(m, 8H), 1.35–1.55(m, 4H),3.20(s,2H), 3.55(s, 3H), 3.75(brs,2H), 3.80–4.00(m, 2H), 4.40–4.70(m, 3H),5.65(s, 1H), 6.50(s, 1H),6.95–7.50(m, 10H), 7.55(s, 1H) Meth41 46

(300MHz, CD₃OD) 0.75–0.85(m,6H), 1.05–1.3(m, 8H), 1.4–1.6(m,4H), 2.2(s,3H), 3.25(2H), 3.7–3.95(m, 4H), 4.7(ABq, 2H), 5.5(s,1H), 6.7(s, 1H),6.75–7.35(m, 9H),7.4(s, 1H) Meth65 47

783.5 Meth66 48

802.7 Meth68 49

(500MHz, CD₃OD) 0.82(brt, 6H),1.05–1.26(m, 8H), 1.42–1.56(m,4H),3.27(brs, 2H), 3.6–3.75(m,2H), 4.58(ABq, 2H), 5.41(s, 1H),6.73–6.82(m,3H), 7.0(d, 2H), 7.05(dd, 1H), 7.25–7.36(m, 3H), 7.41(brd, 2H), 7.48(d,1H); m/z 608.3 Ex119

Example 501,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineammonium salt.

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 22; 150 mg, 0.30 mmol) and2-((2′R)-2′-amino-2′-phenylethanoylamino)ethanesulphonic acid (Method28; containing DIPEA hydrochloride, 150 mg, 0.36 mmol) was dissolved inDMF (6 ml). DIPEA (0.2 ml, 1.15 mmol) and TBTU (114 mg, 0.36 mmol) wereadded and the mixture was stirred for 2 hours at room temperature. Thesolvent was evaporated at reduced pressure. The residue was purified bypreparative HPLC using an MeCN/ammonium acetate buffer gradient (5/95 to100/0) as eluent to give the title compound 73 mg (32%). NMR (CD₃OD)0.75–0.85 (m, 6H), 1.0–1.3 (m, 8H), 1.3–1.6 (m, 4H), 2.16 (s, 3H),2.85–3.0 (m, 2H), 3.24 (brs, 2H) 3.5–3.85 (m, 4H), 4.70 (ABq, 2H), 5.47(s, 1H), 6.71 (s, 1H), 6.97 (brt, 1H), 7.11 (brd, 2H), 7.23–7.45 (m,8H); m/z 746.2.

Example 511,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineAmmonium Salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 17; 49 mg, 0.10 mmol) and2-((2′R)-2′-amino-2′-phenylethanoylamino)ethanesulphonic acid (Method28; containing DIPEA hydrochloride; 52 mg, 0.12 mmol) was dissolved inDMF(2 ml). DIPEA (0.071 ml, 0.41 mmol) and TBTU (39 mg, 0.12 mmol) wasadded and the mixture was stirred for 2 hours at room temperature. Thesolvent was evaporated at reduced pressure. The residue was purified bypreparative HPLC using an MeCN/ammonium acetate buffer gradient (5/95 to100/0) as eluent to give the title compound 59 mg (78%). NMR (CD₃OD)0.74–0.90 (m, 6H), 0.98–1.3 (m, 4H), 1.35–1.6 (m, 4H), 2.16 (s, 3H),2.85–3.02 (m, 2H), 3.23 (brs, 2H) 3.52–3.90 (m, 4H), 4.70 (ABq, 2H),5.47 (s, 1H), 6.71 (s, 1H), 6.96 (brt, 1H), 7.09 (brd, 2H), 7.21–7.48(m, 8H); m/z 718.4.

Example 521,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N-(ethoxycarbonmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 72; 44 mg, 0.063 mmol) was dissolved in THF: H₂O, 1:1, (2 ml)and NaOH (1 M, 0.126 mmol) was added. The mixture was stirred at ambienttemperature for 1 hour. The reaction mixture was acidified with HCl (1M), diluted to 10 ml and extracted with DCM (3×10 ml). The combinedorganic layers were dried (MgSO₄) and the solvent was evaporated to givethe title compound 33 mg (78%). NMR (300 MHz) 0.78–0.85 (m, 6H),1.02–1.70 (m, 8H), 2.20 (s, 3H), 3.15/3.21 (ABq, 2H), 3.78 (m, 2H),3.94/4.20 (dABq, 2H), 4.64 (q, 2H), 5.91 (d, 1H), 6.65 (s, 1H),6.98–7.52 (m, 11H), 8.17 (d, 1H).

Example 531,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N-(1″-carboxy-1″-phenylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesised from1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N-(1″-methoxycarbonyl-1″-phenylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 73) by the procedure of Example 52. NMR (500 MHz) 0.76–0.84 (m,6H), 1.05–1.73 (m, 8H), 2.14 (s, 3H), 3.16 (m, 2H), 3.74 (m, 2H), 4.48(m, 2H), 5.53 (d, 2H), 5.96 (d, 2H), 6.63 (s, 1H), 6.97–7.48 (m, 13H),7.86 (m, 1H), 8.17 (m, 1H).

Example 541,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{1-[N-((R)-α-carboxybenzyl)carbamoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3ethyl-5-phenyl-7-bromo-8-{1-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoyl]ethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 10, 0.050 g, 7.6×10⁻⁵ mol) in DMF (4 ml) was added sodiumthiomethylate (0.021 g, 3.0×10⁻⁴ mol) and the solution was stirred for 4hours at ambient temperature. The mixture was concentrated and theresidue was partitioned between water and ether. The aqueous phase wasextracted two more times with ether and the combined organic extractswere dried (MgSO₄), concentrated and purified by HPLC. The titlecompound was obtained in 0.030 g (63%) as a white solid. NMR (CD₃OD)0.75–0.90 (m, 6H), 1.00–1.30 (m, 4H), 1.40–1.70 (m, 7H), 2.15 (d, 3H),3.10–3.30 (m, 2H), 3.55–3.95 (m, 2H), 4.80–4.95 (m, 2H), 5.30 (d, 1H),6.70–7.50 (m, 12H); m/z 625.3.

Example 551,1-Dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{α-[N-((R)-α-carboxybenzyl)carbamoyl]benzyloxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-ethyl-3-butyl-5-phenyl-7-methylthio-8-{α-[N-((R)-α-carboxybenzyl)carbamoyl]benzyloxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 11; 0.018 g, 2.5×10⁻⁵ mol) in DMF (3 ml) was added sodiumthiomethylate (0.007 g, 1.0×10⁻⁴ mol) and the solution was stirred for 4hours at ambient temperature. The mixture was concentrated and theresidue was partitioned between water and ether. The aqueous phase wasextracted two more times with ether and the combined organic extractswere dried (MgSO₄), concentrated and purified by HPLC. The titlecompound was obtained in 0.015 g (89%) as a white solid. NMR (CD₃OD)0.70–0.85 (m, 6H), 1.00–1.25 (m, 4H), 1.35–1.65 (m, 4H), 2.20 (d, 3H),3.10–3.20 (m, 2H), 3.50–3.85 (m, 2H), 5.30 (d, 1H), 5.80 (d, 1H), 6.70(s, 1H), 6.90–7.65 (m, 16H).

Example 561,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid(Method 80; 32.5 mg, 0.119 mmol) was mixed with DMF (4 ml) andN-methylmorpholine (30 μl, 0.272 mmol). A clear solution was obtainedand1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 22; 50 mg, 0.099 mmol) and TBTU (38 mg, 0.119 mmol) were addedsuccessively. The reaction was stirred at ambient temperature for 30 minand the DMF was removed. The crude product was purified by preparativeHPLC using an MeCN/ammonium acetate buffer (1:1). Lyophilisation gave 55mg of the title compound (71%). NMR (500 MHz, MeOD) 0.78–0.86 (m, 6H),1.0–1.3 (m, 8H), 1.4–1.6 (m, 4H), 2.15 (s, 3H), 2.85–3.00 (m, 2H), 3.25(s, 2H), 3.55–3.68 (m, 2H), 3.75 (brs, 2H), 4.65 (ABq, 2H), 5.36 (s,1H), 6.70 (s, 1H), 6.75 (d, 2H), 6.98 (t, 1H), 7.12 (d, 2H), 7.22 (d,2H) 7.28 (t, 2H), 7.4 (s, 1H); m/z 762.

Examples 57–58

The following compounds were synthesised by the procedure of Example 56using the appropriate starting material except that the reaction wasleft to proceed for 64 hours (Example 57) or 2 hours (Example 58) andthe product was purified by preparative HPLC using an MeCN/ammoniumacetate buffer gradient (45/55 to 60/40) as eluent.

Ex Compound NMR(CD₃OD) and m/z SM 57

Enantiomer 1 0.75–0.84(m, 6H) 1.00–1.27(m,4H), 1.37–1.64(m, 4H)2.14(s,3H), 2.86–3.00(m, 2H), 3.22(s,2H), 3.53–3.68(m, 2H), 3.85brd,2H), 4.68(ABq, 2H), 5.35(s, 1H),6.70(s, 1H), 6.75(d, 2H),6.95(t,1H), 7.08(d, 2H), 7.20–7.29(m,4H), 7.37(s, 1H); m/z 751(M+NH₄ ⁺)Meth23 58

Enantiomer 2 0.77–0.85(m, 6H)1.06–1.27(m,4H), 1.40–1.62(m, 4H)2.17(s,3H), 2.87–3.00(m, 2H), 3.24(s,2H), 3.56–3.68(m, 2H),3.75(brd,2H), 3.56–3.68(m, 2H), 3.75(brd,2H), 4.71(ABq, 2H), 5.37(s,1H),6.72(s, 1H), 6.77(d, 2H), 6.97(t,1H), 7.10(d, 2H), 7.23(d, 2H),7.28(t, 2H), 7.40(s, 1H); m/z 751(M+NH₄ ⁺) Meth24

Example 591,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 38;66.8 mg, 0.109 mmol) and β-alanine ethylester hydrochloride (23.0 mg,0.15 mmol) was dissolved in DCM (2.5 ml) and N-methyl morpholine (0.07ml, 0.64 mmol) was added. After stirring at ambient temperature for 5min TBTU (45.6 mg, 0.142 mmol) was added followed by stirring for 2hours. The reaction mixture was filtered through a short column andconcentrated. The crude ester was dissolved in THF (1.5 ml) and water(1.5 ml) and NaOH (1 M, 0.20 mmol) was added. After stirring at ambienttemperature for 1 hour the reaction was quenched with 1 M HCl. Thereaction mixture was diluted with water (10 ml) and extracted with DCM(3×5 ml). The organic layers was concentrated and purified withpreparative HPLC to give the title compound (60 mg, 81%). NMR (300 MHz)0.80 (m, 6H), 1.00–1.70 (m, 8H), 2.17 (s, 3H), 2.48 (m, 2H), 3.17 (ABq,2H), 3.35 (m, 1H), 3.57 (m, 1H), 3.70 (m, 2H), 4.62 (ABq, 2H), 5.77 (d,1H), 6.64 (s, 1H), 6.98 (t, 1H), 7.06 (d, 2H), 7.28 (m, 4H), 7.42 (m,3H), 7.56 (m, 1H), 8.10 (m, 1H).

Examples 60–63

The following compounds were synthesised by the procedure of Example 59using the appropriate starting material.

Ex Compound NMR SM 60

0.81(m, 6H), 1.00–1.95(m, 10H),2.22(s, 3H), 3.37(m, 2H), 3.18(ABq, 2H),3.48(m, 2H), 3.75(m,2H), 4.66(q, 2H), 5.75(d, 1H), 6.67(s, 1H), 7.00(t,1H), 7.09(m, 2H),7.20(m, 1H), 7.30(m, 4H), 7.44(m,2H), 8.25(m, 1H) Ex3861

(300MHz, DMSO-d₆) 0.74(m, 6H),0.95–1.50(m, 12H), 2.16(s, 3H),2.28(t,2H), 3.24(m, 2H), 4.74(q,2H), 5.33(d, 1H), 6.69(m, 2H), 6.85(t, 1H),6.99(m, 2H), 7.16(m, 4H),8.33–8.45(m, 2H) Ex2 62

(300MHz) 0.81(m, 6H), 1.00–1.74(m, 14H), 2.22(s, 3H), 2.31(m,2H),3.10–3.35(m, 4H), 3.73(m, 2H),4.62(ABq, 2H), 5.64(d, 1H), 6.39(brs,1H), 6.67(s, 1H), 6.96–7.10(m,3H), 7.25–7.48(m, 7H), 8.21(d, 1H) Ex38 63

0.81(m, 6H), 1.03–1.55(m, 12H),2.19(s, 3H), 2.55(m, 2H), 3.18(m,2H),3.46(m, 1H), 3.58(m, 1H),3.74(m, 2H), 4.64(ABq, 2H), 5.80(m, 1H),6.64(s, 1H), 7.01(t, 1H),7.08(d, 2H), 7.30(m, 5H), 7.44(m,3H), 8.11(m,1H) Ex1

Example 641,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-methoxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(t-butoxycarbonyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 78; 48 mg, 0.070 mmol), bromoethyl(trimetylammoniumbromide) (57mg, 0.230 mmol), tetrabutylammonium bromide (3 mg, 0.009 mmol) andCs₂CO₃ (71 mg, 0.22 mmol) were added to CH₃CN (1.0 ml) and the reactionmixture was heated at reflux overnight. The solvent was evaporated andthe residue was added to water (10 ml), extracted with DCM (3×5 ml) anddried (MgSO₄). The crude ester was dissolved in DCM (2.5 ml), TFA (0.3ml) was added and the reaction mixture was stirred at room temperatureovernight. The solvents were evaporated and the crude product waspurified with preparative HPLC to give the title compound (23 mg, 51%).NMR (DMSO-d₆) 0.74 (m, 6H), 0.94–1.60 (m, 8H), 2.17 (s, 3H) 3.25 (m,2H), 3.69 (s, 3H), 4.70 (ABq, 2H), 4.95 (brs, 1H), 6.71 (s, 1H), 6.83(m, 3H), 6.97 (d, 2H), 7.20 (m, 4H), 7.27 (s, 1H), 8.37 (brs, 1H).

Example 651,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(α-[N′-(2-sulhoethyl)carbamoyl]-α-methylbenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineammonium salt

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(α-carboxy-α-methylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 18; 27 mg, 0.041 mmol) was dissolved in DCM (2 ml). Taurinetetrabutylammonium salt (45 mg, 0.123 mmol) and TBTU (16 mg, 0.050 mmol)was added successively and the mixture was stirred for 5 hours atambient temperature. The solvent was evaporated and the product waspurified by preparative HPLC using an MeCN/ammonium acetate buffer(50/50) as eluent. Lyophilisation gave the title compound in 62% yield(20 mg). NMR showed 16% of the product to remain as a tetrabutylammoniumsalt. NMR (500 MHz) 0.75–0.9 (m, 6H), 1.0–1.3 (m, 8H), 1.3–1.6 (m, 4H),1.95 (s, 3H), 2.1 (s, 3H), 2.9 (brs, 2H), 3.05 (brs, 2H), 3.55 (ABd,2H), 3.75 (brs, 2H), 4.55 (ABq, 2H), 6.6 (s, 1H), 6.9–7.6 (m, 12H),8.2–8.3 (brs, 1H); m/z 777 (M+NH4⁺).

Examples 66–67

The following compounds were synthesised by the procedure of Example 65using the appropriate starting material.

Ex Compound NMR(CD₃OD) and M/z SM 66

777(M+NH₄ ⁺) Ex1 67

0.75–0.85(m, 6H), 1.02(t, 12H),1.05–1.3(m, 4H), 1.3–1.7(m, 20H),2.17(s,3H), 2.85–2.99(m, 2H),3.19–3.26(m, 10H), 3.52–3.92(m,4H), 4.71(ABq, 2H),5.47(s, 1H),6.72(s, 1H), 6.96(t, 1H), 7.09(brd,2H), 7.23–7.44(m, 8H);m/z 735.2(M+NH₄ ⁺) Ex25

Example 681,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]-α-methylbenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(methoxycarbonylmethyl)carbamoyl]-α-methylbenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 44; 20 mg, 0.028 mmol) was dissolved in 2.5 ml of a THF/watermixture (4/1). LiOH (2 mg, 0.084 mmol) was added and the mixture wasstirred for 1 hour at ambient temperature. The title compound waspurified with preparative HPLC using an MeCN/ammonium acetate buffer(50/50) as eluent. The MeCN was evaporated and the remaining buffer wasacidified with acetic acid. Lyophilisation gave 10 mg product (51%). NMR0.7–0.9 (m, 6H), 1.0–1.35 (m, 8H), 1.35–1.6 (m, 4H), 2.0 (s, 3H), 2.2(s, 3H), 3.2 (brs, 2H), 3.65–3.85 (brs, 2H), 3.9–4.1 (d, 2H), 4.5–4.7(ABq, 2H), 6.6 (s, 1H), 6.8 (brs, 1H), 6.9–7.5 (m, 11H), 8.1 (s, 1H);m/z 727 (M+NH₄ ⁺).

Example 691,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[α-carboxy-2-fluorobenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 15; 20 mg, 0.030 mmol), taurine tetrabutylammonium salt (20 mg,0.054 mmol) and DIPEA (25 mg, 0.19 mmol) was dissolved in DMF (0.4 ml).TBTU (15 mg, 0.047 mmol) was added and the mixture was stirred for 30min at room temperature. The product was separated from the reactionmixture by preparative HPLC using MeCN/ammonium acetate buffer (50:50)as eluent. 7 mg (29%) of the title compound was obtained. M/z=764.5.

Example 701,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-(R)-{α-[(N′-(R)-{α-[N″-(carboxymethyl)carbamoyl]benzyl}carbamoyl)methylcarbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 43; 35 mg, 0.050 mmol) and (R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 86; 20 mg, 0.076 mmol) were dissolved inDCM (2 ml) and 2,6-lutidine (0.03 ml, 0.26 mmol) was added. Afterstirring at ambient temperature for 5 min, TBTU (20 mg, 0.062 mmol) wasadded and stirring was continued for 3 hours. The reaction mixture wasfiltered through a column using DCM: EtOAc; 3:1 as eluent. The t-butylester was then dissolved in DCM (6 ml) and TFA (1 ml) was added. Afterstirring at ambient temperature overnight the solvents were evaporated.Toluene was added and evaporated twice. No further purification wasnecessary to give the title compound (40 mg, 93%). NMR (500 MHz,DMSO-d₆) 0.75 (m, 6H), 0.95–1.50 (m, 12H), 2.16 (s, 3H), 3.25 (m, 2H),3.75 (m, 2H), 3.90 (dd, 1H), 4.73/4.84 (ABq, 2H), 5.54 (m, 2H), 5.58 (d,1H), 6.68 (s, 1H), 6.85 (t, 1H), 6.99 (d, 2H), 7.18–7.46 (m, 13H),8.51–8.73 (m, 4H).

Example 711,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 22; 61 mg, 0.12 mmol) andmethyl(2S)-amino(4-hydroxyphenyl)acetate hydrochloride (31 mg, 0.14mmol) were dissolved in DCM (4 ml) and 2,6-lutidine (0.04 ml, 0.34 mmol)was added. After stirring at room temperature for 5 min TBTU (3 mg, 0.17mmol) was added and stirring was continued for 2 hours. The reactionmixture was filtered through a short column. The crude methyl ester wasdissolved in THF (1.5 ml) and water (1.0 ml) and NaOH (aq., 1 M, 0.39mmol) was added. The reaction mixture was stirred at room temperaturefor 8 hours, quenched with HCl (1 M) and extracted with DCM (3×5 ml).The collected organic layers were concentrated and purified withpreparative HPLC using MeCN/ammonium acetate buffer (50:50) to give thetitle compound (57 mg, 72%). NMR (500 MHz, CD₃OD) 0.81 (m, 6H),1.05–1.26 (m, 8H), 1.40–1.55 (m, 4H), 2.17 (s, 3H), 3.24 (brs, 2H), 3.74(brs, 1H), 4.66 (ABq, 2H), 6.70–6.75 (m, 3H), 6.99 (t, 1H), 7.11 (d,2H), 7.22–7.30 (m, 4H), 7.40 (s, 1H).

Example 721,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-(S)-{α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepineammonium salt

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 71; 31 mg, 0.047 mmol) and tetrabutylammonium taurine (57 mg,0.155 mmol) were dissolved in DCM (2 ml). After stirring at roomtemperature for 5 min TBTU (24 mg, 0.075 mmol) was added and stirringwas continued for 6 hours. The solvent was evaporated and the residuewas purified with preparative HPLC (twice to remove alltetrabutylammonium salt) using MeCN/ammonium acetate buffer to give thetitle compound 6 mg (16%). M/z 762.2.

Example 73 and Example 741,1-Dioxo-3-(R/S)-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-(R)-{α-[N′-(R)-(2-imidazol-5-yl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 38; 56.4 mg, 0.092 mmol) and methyl D-histidinatedihydrochloride (25.2 mg, 0.104 mmol) were added to DCM (3 ml). N-methylmorpholine (0.05 ml, 0.41 mmol) was added followed by TBTU (40 mg, 0.12mmol). The reaction mixture was stirred at 4° C. for 1 hour 30 min andat room temperature for 3 hours. More TBTU (15 mg, 0.047 mmol) and DIPEA(0.025 ml, 0.14 mmol) were added and the reaction mixture was stirred atroom temperature, for another 30 min. The solvent was evaporated and theresidue was filtered through a short column with MeOH as eluent. Thecrude methyl ester was dissolved in THF (1.0 ml) and water (1.0 ml) andNaOH (aq., 1 M, 0.15 mmol) was added. The reaction mixture was stirredat room temperature for 2 hours and was quenched with HCl (1 M). Thesolvents were evaporated the residue was purified with preparative HPLCusing MeCN/ammonium acetate buffer. The compound eluted as two peaks,assumed to be the two diastereomers. First peak (10 mg, 14%). Secondpeak (16.8 mg, 24%). First peak: NMR (DMSO-d₆) 0.74 (m, 6H), 0.95–1.60(m, 8H) 2.17 (s, 3H), 2.82 (m, 2H), 3.23 (m, 2H), 4.27 (m, 1H), 4.80(ABq, 2H), 5.60 (d, 1H), 6.55 (brs, 1H), 6.70 (s, 1H), 6.84 (t, 1H),6.96 (d, 2H), 7.14–7.28 (m, 6H), 7.33 (s, 1H), 7.44 (brs, 1H), 8.54 (d,1H), 8.60 (brs, 1H); m/z 748.4. Second peak: NMR (DMSO-d₆) 0.74 (m, 6H),0.95–1.60 (m, 8H), 2.17 (s, 3H), 2.92 (dABq, 2H), 3.23 (m, 2H), 4.41 (m,1H), 4.79 (ABq, 2H), 5.60 (d, 1H), 6.70 (s, 1H), 6.78 (s, 1H), 6.84 (t,1H), 6.96 (d, 2H), 7.16–7.34 (m, 6H), 7.40 (m, 2H), 7.55 (s, 1H), 8.55(d, 1H), 8.71 (d, 1H); m/z 748.4.

Example 751,1-Dioxo-3,3-dibutyl-5-(4-t-butylphenyl)-7-methylthio-8-(N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was isolated as a byproduct in synthesis of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 43). Approximately 1 g of this compound was purified withpreparative HPLC (MeCN/ammonium acetate buffer (50:50)) to give thetitle compound (32 mg). NMR (500 MHz, DMSO-d₆) 0.73 (m, 6H), 0.90–1.40(m, 12H), 1.24 (s, 9H), 2.16 (s, 3H), 3.23 (m, 2H), 3.65/3.75 (dABq,2H), 4.72/4.82 (ABq, 2H), 5.60 (d, 1H), 6.65 (s, 1H), 6.97 (d, 2H),7.23–7.35 (m, 6H), 7.45 (d, 2H), 8.58 (d, 1H), 8.62 (t, 1H).

Example 76 1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-(N-((R)-α-carboxybenzylmethylthio)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 81; 38 mg, 0.080 mmol) and D-phenylglycine methyl esterhydrochloride (24 mg, 0.12 mmol) were dissolved in DCM (2 ml) andN-methyl morpholine (0.05 ml, 0.42 mmol) was added. After stirring atroom temperature for 5 min TBTU (44 mg, 0.14 mmol) was added andstirring was continued for 2 hours. The reaction mixture was filteredthrough a short column. The resulting product was dissolved in THF (1ml) and water (1 ml) and NaOH (aq., 0.2 ml, 1 M) was added and thereaction mixture was stirred at room temperature for 2 hours. Thereaction was quenched with HCl (1 M), diluted with water (10 ml) andextracted with DCM (3×3 ml). Purification with preparative HPLC yieldedthe title compound (40 mg, 82%). NMR (DMSO-d₆) 0.75 (m, 6H), 0.96–1.60(m, 8H), 3.22 (m, 2H), 3.56 (ABq, 2H), 3.89 (s, 3H), 4.81 (d, 1H), 6.78(t, 1H), 6.83 (d, 2H), 6.89 (s, 1H), 7.11–7.23 (m, 7H), 7.31 (s, 1H),8.37 (m, 1H).

Example 771,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-[N-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonylmethylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 82; 21 mg, 0.038 mmol) and phenylglycine methyl esterhydrochloride (12 mg, 0.061 mmol) were dissolved in DCM (1.5 ml) andN-methyl morpholine (0.02 ml, 0.19 mmol) was added. After stirring atambient temperature for 5 min TBTU (18 mg, 0.056 mmol) was added andstirring was continued for 2 hours. The reaction mixture was filteredthrough a short column. The crude diester was dissolved in THF (1 ml)and water (1 ml) and NaOH (aq., 0.1 ml, 1 M) was added. The reactionmixture was stirred at ambient temperature for 2 hours, quenched withHCl (1 M), diluted with water (10 ml) and extracted with DCM (3×3 ml).The collected organic layers were concentrated and purified withpreparative HPLC using MeCN/ammonium acetate buffer (30:70→40:60) togive the title compound (20 mg, 80%). NMR (CD₃OD) 0.80 (m, 6H),1.03–1.26 (m, 4H), 1.38–1.65 (m, 4H), 1.96 (s, 3H), 3.20 (s, 2H), 3.44(s, 2H), 3.67 (brs, 1H), 3.76 (brs, 1H), 4.67 (ABq, 2H), 5.29 (s, 1H),6.89 (s, 1H), 6.92 (t, 1H), 7.05 (d, 2H), 7.19–7.32 (m, 5H), 7.41 (s,1H), 7.45 (d, 2H).

Example 781,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(R)-(α-{N′-[(R)-N″-(2-hydroxy-1-carboxyethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 43; 50 mg, 0.072 mmol), tert-butyl o-(tert-butyl)-D-serinatehydrochloride (22 mg, 0.087 mmol) and N-methylmorpholine (40 mg, 0.40mmol) were dissolved in DCM (1 ml). TBTU (29 mg, 0.090 mmol) was addedand the mixture was stirred for 1 hour at room-temperature. The reactionmixture was evaporated and the residue was filtered through a shortcolumn (DCM: EtOAc, 1:4). The substance obtained (ca. 60 mg) wasdissolved in DCM (1 ml). TFA (0.59 g, 5.2 mmol) was added and themixture was stirred for 2 hours at room temperature. The solvent wasevaporated and the residue was purified by preparative HPLC usingMeCN/ammonium acetate buffer (50:50) as eluent. 38 mg (72%) of the titlecompound was obtained. NMR (300 MHz, DMSO-d₆) 0.7–0.8 (m, 6H), 0.9–1.5(m, 12H), 2.2 (s, 3H), 3.2–3.9 (m, 10H), 4.2 (brs, 1H), 4.8 (ABq, 2H),5.6 (d, 1H), 6.7 (s, 1H), 6.8–7.5 (m, 11H), 8.0 (d, 1H), 8.6 (d, 1H),8.7 (t, 1H).

Example 791,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(R)-(α-{N′-[(S)-N″-(2-hydroxy-1-carboxyethyl)carbamoylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 43; 50 mg, 0.072 mmol), tert-butyl O-(tert-butyl)-L-serinatehydrochloride (22 mg, 0.087 mmol) and N-methylmorpholine (40 mg, 0.40mmol) were dissolved in DCM (1 ml). TBTU (29 mg, 0.090 mmol) was addedand the mixture was stirred for 1 h at room temperature. The reactionmixture was evaporated and the residue was filtered through a shortcolumn (DCM: EtOAc, 1:4). The substance obtained (ca. 60 mg) wasdissolved in DCM (1 ml). TFA (0.44 g, 3.9 mmol) was added and themixture was stirred for 18 hours at room temperature. The solvent wasevaporated and the residue was purified by preparative HPLC usingMeCN/ammonium acetate buffer (50:50) as eluent. 33 mg (63%) of the titlecompound was obtained. NMR (300 MHz, DMSO-d₆) 0.7–0.8 (m, 6M), 0.9–1.5(m, 12H), 2.2 (s; 3H), 3.2–3.9 (m, 10H); 4.2 (m, 1H), 4.8 (ABq, 2H), 5.6(d, 1H), 6.7 (s, 1H), 6.8–7.5 (m, 11H), 7.9 (d, 1H), 8.6 (d, 1H), 8.7(t, 1H).

Example 801,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(1,1-dicarboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 38; 50 mg, 0.082 mmol), dimethylaminomalonate (60 mg, 0.13mmol) and N-methylmorpholine (55 μl, 0.5 mmol) were dissolved in DCM (3ml), TBTU (42 mg, 0.13 mmol) was added and the mixture was stirred for15 mins. The solvent was evaporated under reduced pressure. The residuewas dissolved in ethanol (95%) (2 ml) and a solution of NaOH (80 mg, 2mmol) in water (80 μl) was added. The reaction mixture was stirred for 4hours. The mixture was neutralized with acetic acid. The solvent wasevaporated under reduced pressure and the residue was purified bypreparative HPLC using-MeCN/ammonium acetate buffer (40:60) as eluent.The collected fractions were lyophilised to obtain 4 mg (7%) of thetitle compound. NMR (300 MHz, CD₃OD) 0.75–0.9 (m, 6H), 1.0–1.3 (m, 4H),1.4–1.65 (m, 4H), 2.15 (s, 3H), 3.25 (s, 2H), 3.7 (brs, 2H), 4.65–4.8(m, 2H), 5.75 (s, 1H), 6.75 (s, 1H), 6.9–7.55 (m, 11H).

Examples 81–87

The following compounds were synthesised by the procedure of Example 80using the appropriate starting material except that 2,6-lutedine wasused instead of N-methylmorpholine and the ration of eluent wasMeCN/ammonium acetate buffer (45:55). Reaction time at each stage variedslightly.

Ex Compound NMR(300MHz, CD₃OD) SM 81

(500MHz) 0.8–0.95(m, 6H), 1.05–1.35(m, 4H), 1.4–1.7(m, 4H), 2.2(s,3H),3.25(s, 2H), 3.7–3.9(m, 4H),4.4–4.45(m, 1H), 4.7–4.8(m, 2H),5.7(s, 1H),6.75(s, 1H), 6.95–7.6(m,11H) Ex38 82

0.75–0.9(m, 6H), 1.05–1.3(m, 4H),1.4–1.6(m, 4H), 2.15(s, 3H),3.25(s,2H), 3.7–3.95(m, 4H), 4.25–4.3(m,1H), 4.75(ABq, 2H), 5.65(s,1H),6.75(s, 1H), 7.95–7.55(m, 11H) Ex38 83

0.75–0.9(m, 6H), 1.05–1.35(m, 8H),1.4–1.6(m, 4H), 2.15(s, 3H),3.25(s,2H), 3.7–3.9(m, 4H), 4.35–4.45(m,1H), 4.7(ABq, 2H), 5.7(s, 1H),6.75(s, 1H), 6.95–7.55(m, 11H) Ex 1 84¹

0.75–0.9(m, 6H), 1.05–1.3(m, 8H),1.4–1.6(m, 4H), 2.15(s, 3H),3.25(s,2H), 3.7–3.9(m, 4H), 3.3–3.4(m,1H), 4.7(ABq, 2H), 5.65(s, 1H),6.7(s, 1H), 6.95–7.55(m, 11H) Ex 1 85²

0.75–0.9(m, 6H), 1.05–1.3(m, 8H),1.4–1.6(m, 4H), 3.25(s, 3H), 3.6–3.9(m,6H), 4.3–4.5(m, 2H), 4.7(ABq,2H), 5.65(s, 1H), 6.7(s, 1H), 6.95–7.5(m,11H) Ex83 86³

0.75–0.9(m, 6H), 1.05–1.3(m, 8H),1.4–1.6(m, 4H), 2.15(s, 3H),3.25(s,2H), 3.6–3.9(m, 6H), 4.35–4.5(m,2H), 4.7(ABq, 2H), 5.6(s, 1H),6.7(s, 1H), 6.95–7.55(m, 11H) Ex83 87⁴

0.75–0.9(m, 6H), 1.05–1.3(m, 8H),1.4–1.6(m, 4H), 2.2(d, 3H),3.15–3.35(m, 5H), 3.5–3.85(4H), 4.4–4.5(m, 1H), 4.6–4.7(m, 2H), 5.6(s,1H),6.7(s, 1H), 6.95–7.55(m, 11H) Ex 1 ¹Eluent ratio (55:45); ²Eluentratio - variable gradient; ³Eluent ratio (50:50); ⁴Eluent ratio (60:40)

Example 881,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 87; 55.2 mg, 0.064 mmol) was dissolved in THF (2 ml) and 0.5 mlwater. LiOH (3.1 mg, 0.127 mmol) was added and the mixture was stirredfor 1 hour. Water (1 ml) was added and the mixture was acidified with0.1M HCl and extracted with DCM (3×2 ml). The DCM phase was dried withand concentrated. The solid product was co-evaporated with diethyl etherand dissolved in HPLC grade water. Lyophilisation gave the titlecompound as a white solid in 68% yield (28 mg). NMR 0.77–0.85 (m, 6H),1.03–1.25 (m, 8H), 1.34–1.57 (m, 4H), 2.16 (s, 3H), 3.18 (brs, 2H), 3.75(brs, 2H), 4.65 (ABq, 2H), 5.7 (d, 1H), 6.63 (s, 1H), 7.0 (t, 1H), 7.1(d, 2H), 7.26–7.48 (m, 8H), 7.85 (d, 1H); m/z 639.

Example 891,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(S)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(S)-α-[N′-(methoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 88; 19 mg, 0.027 mmol) was hydrolysed by LiOH (1.3 mg, 0.054mmol) in THF (1 ml) and water (0.3 ml). After 1 hour water (3 ml) wasadded and the mixture acidified using 0.1M HCl and extracted with DCM(3×3 ml). The organic layer was dried and evaporated yielding 16 mg (82%yield) of the title compound. NMR 0.77–0.85 (m, 6H), 1.0–1.3 (m, 8H),1.34–1.57 (m, 4H), 2.17 (s, 3H), 3.18 (s, 2H), 3.75 (brs, 2H), 3.9–4.20(m, 2H), 4.65 (ABq, 2H), 5.87 (m, 1H), 6.63 (s, 1H), 6.98–7.50 (m, 12H),8.12–8.20 (m, 1H); m/z 696.

Example 901,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(S)-α-[N′-(2-sulphoethylcarbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepinesodium salt

1,1-Dioxo-3,3—dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 88; 41 mg, 0.064 mmol) was dissolved in 3 ml DCM. Taurinetetrabutylammonium salt (70 mg, 0.191 mmol) and TBTU (25 mg, 0.078 mmol)were added successively and the mixture was stirred overnight at ambienttemperature. The solvent was evaporated and the product was purified bypreparative HPLC using an MeCN/ammonium acetate buffer gradient (45/55to 55/45) as eluent. Lyophilisation of the collected fractions and thenion-exchange chromatography over 4 g Amberlite CG 120, Na⁺-form, gavethe title compound in 85% yield (42 mg). NMR 0.7–0.8 (m, 6H), 0.9–1.2(m, 8H), 1.3–1.5 (m, 4H), 2.0 (s, 3H), 2.9–3.2 (m, 2H+2H), 3.3–3.8 (m,2H+2H), 4.4–4.7 (m, 2H), 5.6 (m, 1H), 6.57 (s, 1H), 6.9–7.5 (m, 11H),7.8–8.1 (m, 2H), m/z 746.

Example 91

The following compound was synthesised by the procedure of Example 90using the appropriate starting material except the product was purifiedusing a buffer gradient of 40/60 to 70/30 and then lyophilised to givethe ammonium salt.

Ex Compound NMR(CD₃OD) and m/z SM 91

0.76–0.84(m, 6H), 1.03–1.27(m, 8H),1.38–1.55(m, 4H), 2.15(s, 3H),2.95(t,2H), 3.24(s, 2H), 3.58(dt, 2H), 3.75(brs, 2H), 3.85(ABdd, 2H),4.72(ABq,2H), 5.51(s, 1H), 6.70(s, 1H), 6.97(t,1H), 7.11(d, 2H),7.25–7.40(m, 6H),7.46(d, 2H); m/z 803 Ex43

Example 921,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-[N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepinesodium salt

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepinesodium salt (WO 01/66533; 120 mg, 0.278 mmol) dissolved in DCM (4 ml)was added to a solution ofα-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 86; 90%, 150mg, 0.511 mmol) in DCM (3 ml). 2,6-Dimethylpyridine (65 □l, 0.559 mmol)and TBTU (137 mg, 0.427 mmol) were added and the reaction mixture wasstirred at ambient temperature overnight. The solution was filtered overusing DCM/EtOAc (8/2) as eluent. The solvent was evaporated. DCM (4 ml)and TFA (0.6 ml) were added and the mixture was stirred overnight. Thesolvent was evaporated and the crude product was purified by preparativeHPLC on a Chromasil C₁₈ column. An MeCN/ammonium acetate buffer gradient(50/50 to 100/0) was used as mobile phase. The MeCN was evaporated andlyophilisation gave the title compound in 36% yield (62 mg). NMR0.73–0.82 (m, 6H), 1.00–1.23 (m, 4H), 1.30–1.65 (m, 4H), 3.05–3.18 (m,2H), 3.65 (brs, 2H), 3.75 (ABdd, 2H), 4.46 (ABq, 2H), 5.70 (d, 1H),6.79–7.24 (m, 10H), 7.36 (d, 2H), 7.46 (d, 1H), 7.83 (d, 1H), 8.00 (brs,1H); m/z 622.

Example 93–94

The following compounds were synthesised by the procedure of Example 92using the appropriate starting material except that theHPLC-chromatography was performed on a Chromasil C₈ column and theeluent gradient was 45/55 to 60/40.

Ex Compound NMR(CD₃OD) and m/z SM 93

Enantiomer 1 0.75–0.84(m, 6H) 1.00–1.27(m,4H), 1.38–1.66(m, 4H)2.15(s,3H), 3.22(s, 2H), 3.75(brs, 2H),3.83(ABdd, 2H), 4.69(ABq,2H),5.60(s, 1H), 6.71(s, 1H), 6.96(t,1H), 7.09(d, 2H), 7.23–7.37(m,5H),7.39(s, 1H), 7.46(d, 2H);m/z 668 Meth23;Meth86 94

Enantiomer 2 0.78–0.85(m, 6H) 1.04–1.27(m,4H), 1.41–1.65(m, 4H),2.17(s,3H), 3.24(s, 2H), 3.68(brs, 2H),3.89(ABdd, 2H), 4.72(ABq,2H),5.62(s, 1H), 6.73(s, 1H), 6.97(t,1H), 7.11(d, 2H), 7.26–7.38(m,5H),7.41(s, 1H), 7.48(d, 2H);m/z 668 Meth24;Meth86

Example 951,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(ethoxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of 2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv. Chim.Acta; GE; 75; 8; 1992; 2545–2552; 16 mg, 0.106 mmol) in DCM (2 ml) wasadded at 0° C.1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 38; 50 mg, 0.082 mmol) DIPEA (42 mg, 0.328 mmol) and TBTU (34mg, 0.106 mmol) under argon. The reaction mixture was stirred at roomtemperature for 110 min and then DCM was added and the solution washedwith NaHCO₃ (aq, sat) and brine. The organic layer was dried and thesolvent evaporated under reduced pressure. The residue purified bychromatography and the product eluted with DCM/methanol (100:5). Yield43 mg (71%). NMR (500 MHz) 0.78–0.85 (m, 6H), 1.02–1.54 (m, 12H),1.6–1.75 (br, 1H), 1.8–2.10 (m, 3H), 2.21 (s, 3H), 3.10–3.25 (m, 2H),3.51–3.84 (m, 4H), 3.9–3.99 (m, 1H), 4.01–4.09 (m, 1H), 4.54–4.69 (dd,2H), 5.51 (d, 1H), 6.68 (s, 1H), 6.96–7.02 (m, 1H), 7.03–7.18 (m, 3H),7.25–7.42 (m, 6H), 7.43–7.48 (m, 2H), 8.05–8.15 (m, 1H).

Examples 96–97

The following compounds were synthesised by the procedure of Example 95using the appropriate starting material.

Ex Compound NMR and m/z SM 96

0.76–0.85(m, 6H), 1.00–1.52(m, 12H),1.55–1.75(m, 1H), 1.95–2.12(br,1H),2.20(s, 3H), 3.10–3.25(m, 2H), 3.55–3.85(m, 4H), 3.85–4.00(m, 2H),4.03–4.13(m, 2H), 4.6(q, 2H), 5.64(d, 1H),6.66(s, 1H), 7.78(br, 1H),6.95–7.10(m,3H), 7.23–7.40(m, 6H), 7.43–7.49(m,2H), 8.07(d, 1H); m/z760.3 Ex38 97¹

(600MHz) 0.75–0.82(m, 6H), 1.0–1.42(m, 13H), 1.64(brs, 1H), 2.18(s,3H),3.08–3.24(m, 2H), 3.50–3.84(m, 4H),3.87–4.13(m, 2H), 4.54–4.68(m,2H),5.56–5.62(m, 1H), 6.63(s, 1H), 6.87–7.10(m, 3H), 7.24–7.40(m, 7H),7.43–7.49(m, 2H), 7.98–8.05(m, 1H); m/z730.5 Ex38 ¹Amine: Tetrahedron;EN; 49; 47; 1993; 11055–11064

Example 981,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(ethoxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 95; 27 mg, 0.036 mmol) in ethanol (1.5 ml) was added at 0° C. 2M aqueous NaOH (0.22 ml, 0.44 mmol). The reaction mixture was stirred atroom temperature for 24 hours. Acetic acid (0.2 ml) was added. Thesolvent was evaporated under reduced pressure and the residue wasextracted with DCM/water. The DCM layer was separated, washed withbrine, dried and evaporated under reduced pressure. Recrystallization ofthe residue from DCM/ether/petroleum ether gave the title compound 23 mg(89%). NMR (600 MHz) 0.74–0.82 (m, 6H), 1.0–1.70 (m, 11H), 1.90–2.09 (m,2H), 2.16 (s, 3H), 3.05–3.24 (m, 2H), 3.40–3.85 (m, 4H), 4.50–4.65 (dd,2H), 5.55 (d, 1H), 6.63 (s, 1H), 6.93–7.07 (m, 3H), 7.20–7.50 (m, 9H),8.10 (d, 1H); m/z 716.3.

Example 991,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[(hydroxy)(ethoxy)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[(diethoxy)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 96; 13 mg, 0.017 mmol) in MeCN (0.5 ml) was added 1 M aqueousLiOH (0.171 ml, 0.171 mmol) dropwise. The reaction mixture was stirredat room temperature for 3 days. Acetic acid was added and the solventevaporated under reduced pressure. The crude product was purified bypreparative HPLC using MeCN and ammonium acetate buffer (45:55) aseluent to give the title compound 11 mg (88%). NMR (600 MHz, CD₃OD)0.77–0.84 (m, 6H), 1.00–1.30 (m, 7H), 1.40–1.65 (m, 4H), 2.17 (s, 3H),3.23 (brs, 2H), 3.51 (d, 2H), 3.6–3.85 (m, 4H), 4.70 (dd, 2H), 5.57 (s,1H), 6.72 (s, 1H), 6.96 (t, 1H), 7.09 (d, 2H), 7.25–7.31 (m, 3H),7.32–7.36 (m, 2H), 7.40 (s, 1H), 7.45 (d, 2H); m/z 732.4.

Example 1001,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[(hydroxy)(methyl)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[(ethoxy)(methyl)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 97; 85 mg, 0.12 mmol) in MeCN (2.4 ml) was added at 0° C. 1 Maqueous LiOH (1.17 ml, 1.17 mmol) dropwise. The reaction mixture wasstirred at room temperature for 20 hours. Acetic acid was added and thesolvent evaporated under reduced pressure. The crude product waspurified by column chromatography using DCM/MeOH(Et₃N (100:15:0.2 and100:30:0.2) as eluent to give the title compound 62 mg (76%). NMR(CD₃OD) 0.75–0.84 (m, 6H), 1.0–1.70 (m, 11H), 2.15 (s, 3H), 3.22 (brs,2H), 3.35 (d, 2H), 3.60–3.90 (m, 2H), 4.70 (dd, 2H), 3.55 (s, 1H), 6.71(s, 1H), 6.96 (t, 1H), 7.09 (d, 2H), 7.23–7.38 (m, 5H), 7.40 (s, 1H),7.46 (d, 2H); m/z 702.3

Example 101

The following compound was synthesised by the procedure of Example 100using the appropriate starting material.

Ex Compound NMR(600MHz, CD₃OD) and m/z SM 101

0.76–0.83(m, 6H), 1.05–1.55(m, 15H),1.91–1.99(m, 2H), 2.15(s, 3H),3.24(brs, 2H), 3.40–3.50(m, 2H), 3.66–3.86(m, 2H), 4.69(dd, 2H), 5.42(s,1H), 6.70(s, 1H), 6.92(t, 1H), 7.11(d, 2H), 7.25–7.39(m, 6H), 7.43(d,2H); m/z 744.3 Ex104

Example 1021,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[di-(t-butoxy)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 38; 80 mg, 0.131 mmol) and di-(t-butoxy)phosphorylmethyamine(Tet. Lett.; EN; 33; 1; 1992; 77–80; 37 mg, 0.164 mmol) in DCM (5 ml)was added 2,6-lutidine (28 mg, 0.262 mmol) and TBTU (53 mg, 0.164 mmol).The reaction mixture was stirred at room temperature for 2 hours and 50min. The solvent was evaporated under reduced pressure and the crudeproduct was purified by column chromatography using DCM/MeOH (100:4) aseluent to give the title compound 92 mg (86%). NMR (500 MHz) 0.77–0.86(m, 6H), 1.03–1.75 (m, 26H), 2.22 (s, 3H), 2.10–2.25 (m, 2H), 3.45–3.90(m, 4H), 4.61 (dd, 2H), 5.52 (d, 1H), 5.94 (brs, 1H), 6.67 (s, 1H), 7.0(t, 1H), 7.07 (d, 2H), 7.26–7.48 (m, 8H), 8.12 (d, 1H); m/z 704.22[M-2(t-butyl)+2H].

Example 103

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[di-(hydroxy)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[di-(t-butoxy)phosphorylmethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 102; 72 mg, 0.088 mmol) in DCM (4 ml) was added at 0° C. TFA (1ml). The reaction mixture was stirred at room temperature for 2 hours.The solvent was evaporated under reduced pressure and the residue wasextracted with DCM/water. The organic layer was separated, washed withbrine, dried and evaporated under reduced pressure. The residue wassuspended in ether and the crystals filtered to give the title compound60 mg (97%). NMR (500 MHz, DMSO-d₆) 0.70–0.80 (m, 6H), 0.99–1.61 (m,8H), 2.18 (s, 3H), 2.80–4.0 (m, 6H), 4.80 (dd, 2H), 5.65 (d, 1H), 6.71(s, 1H), 6.80–7.02 (m, 3H), 7.15–7.35 (m, 6H), 7.48 (d, 2H), 8.50–9.20(m, 2H); m/z 704.3

Example 1041,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 1; 60 mg, 0.094 mmol) and2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv. Chim. Acta; GE; 75; 8;1992; 2545–2552; 20 mg, 0.132 mmol) was added at 0° C. 2,6-lutidine (20mg, 0.19 mmol) and TBTU (39 mg, 0.121 mmol) under argon. The reactionmixture was stirred at room temperature for 70 min and then DCM wasadded and the solution washed with water and brine. The organic layerwas dried and the solvent evaporated under reduced pressure. The residuewas purified by column chromatography using DCM/MeOH (100:5) as eluentto give the title compound 67 mg (92%). NMR (300 MHz) 0.74–86 (m, 6H),1.0–1.60 (m, 18H), 1.80–2.05 (m, 2H), 2.20 (s, 3H), 2.17 (s, 2H),3.47–3.80 (m, 4H), 3.88–4.10 (dd, 2H), 5.52 (d, 1H), 6.65 (s, 1H),6.95–7.12 (m, 3H), 7.13–7.42 (m, 7H), 7.43–7.49 (m, 2H), 8.05–8.16 (m,1H); m/z 772.4.

Example 1051,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[N′-(2-mercapto-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α-{N′-[2-(triphenylmethylsulphanyl)-1-(t-butoxycarbonyl)ethyl]carbamoyl}benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 91; 37 mg, 0.036 mmol) in DCM (1 ml) was added at 0° C. TFA (1ml) under argon blanketing. The ice-bath was removed and triethylsilane(42 mg, 0.36 mmol) was added. The reaction mixture was stirred at roomtemperature for 2 hours and then the solvent evaporated under reducedpressure. The crude product was purified by preparative HPLC using MeCNand ammonium acetate buffer (40:60 to 60:40) as eluent to give the titlecompound 16 mg (59%). NMR (500 MHz, CD₃OD) 0.76–0.85 (m, 6H), 1.05–1.60(m, 12H), 2.17 (s, 3H), 2.77–2.92 (m, 2H), 3.24 (brs, 2H), 3.61–3.88 (m,2H), 4.56 (t, 1H), 4.70 (dd, 2H), 5.65 (s, 1H), 6.71 (s, 1H), 6.98 (t,1H), 7.12 (d, 2H), 7.25–7.43 (m, 6H), 7.50 (d, 2H); m/z 742.4.

Example 106

The following compound was synthesised by the procedure of Example 105using the appropriate starting material.

Ex Compound NMR(500MHz, CD₃OD) and m/z SM 106

0.77–0.85(m, 6H), 1.03–1.28(m, 8H),1.38–1.58(m, 4H), 2.15(s, 3H),2.87–3.5(m, 2H), 3.25(s, 2H), 3.75(brs,2H), 4.55(s, 1H), 4.71(dd, 2H),5.66(s, 1H), 6.71(s, 1H), 6.98(t, 1H), 7.12(d, 2H), 7.25–7.43(m, 6H),7.49(d,2H); m/z 742.28 Meth93

Example 1071,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(carboxy)benzyl]carbamoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 90; 77 mg, 0.108 mmol) in DCM (3 ml) was added at 0° C. TFA(0.75 ml). The reaction mixture was stirred at room temperature for 2 hand 45 min. The solvent was evaporated under reduced pressure and thecrude product was purified by preparative HPLC using MeCN and ammoniumacetate buffer (40:60 to 50:50) as eluent to give the title compound 60mg (82%). NMR (500 MHz, CD₃OD) 0.75–0.85 (m, 6H), 1.0–1.25 (m, 4H),1.40–1.64 (m, 4H), 2.75–2.90 (m, 2H), 3.26 (s, 2H), 3.50–3.90 (m, 2H),4.30–4.41 (m, 2H), 5.43 (s, 1H), 6.99 (t, 1H), 7.05–7.13 (m, 3H),7.23–7.34 (m, 5H), 7.45 (d, 2H), 7.52 (s, 1H); m/z 658.

Example 108

The following compound was synthesised by the procedure of Example 107using the appropriate starting material.

Ex Compound NMR(500MHz, CD₃OD) and m/z SM 108

0.78–0.85(m, 6H), 1.02–1.30(m,8H), 1.38–1.58(m, 4H), 1.87(s, 3H),2.15(s,3H), 2.77–2.83(m, 1H),2.87–2.94(m, 1H), 3.24(s, 2H), 3.74(brs, 2H),4.53–4.59(m, 1H), 4.68(dd, 2H), 5.66(s, 1H), 6.71(s, 1H),6.98(t, 1H),7.12(d, 2H), 7.25–7.31(m, 3H), 7.32–7.36(m, 2H), 7.40(s,1H), 7.49(d,2H); m/z 756.23 Meth92

Example 1091,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-S-8-]N-((R)-α-carboxy-4-hydroxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 2; 80 mg, 0.122 mmol) and2-[(methyl)(ethyl)phosphoryl]ethylamine (Helv. Chim. Acta; GE; 75; 8;1992; 2545–2552; 24 mg, 0.159 mmol) in DCM (2 ml) was added 2,6-lutidine(26 mg, 0.244 mmol) and TBTU (51 mg, 0.159 mmol) under argon. Thereaction mixture was stirred at room temperature for 60 min, thendiluted with DCM. The solution was washed with water, brine, dried andthe solvent was evaporated under reduced pressure. The residue waspurified by column chromatography using DCM/MeOH (100:7) as eluent togive the title compound 67 mg (92%). NMR (600 MHz), 0.74–0.80 (m, 6H),1.0–1.55 (m, 18H), 1.82–1.98 (m, 2H), 2.15 (s, 3H), 3.14 (brs, 2H),3.40–3.56 (m, 2H), 3.70 (brs, 2H), 3.89–4.02 (m, 2H), 4.51(dd, 2H), 5.33(t, 1H), 6.61 (s, 1H), 6.65–6.72 (m, 2H), 6.95 (t, 1H), 7.03 (d, 2H),7.12–7.19 (m, 3H), 7.22–7.26 (m, 2H), 7.32 (s, 1H), 8.11 (t, 1H); m/z788.56.

Example 1101,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 104; 37 mg, 0.047 mmol) in MeCN/MeOH (4 ml, 1:1) was added 1 Maqueous LiOH (0.8 ml, 0.8 mmol). The reaction mixture was stirred atroom temperature for 40 min. Acetic acid was added and the solventevaporated under reduced pressure. The crude product was purified bypreparative HPLC using MeCN and ammonium acetate buffer (40:60 and45:55) as eluent to give the title compound 35 mg (96%). NMR (500 MHz,CD₃OD) 0.78–0.85 (m, 6H), 1.06–1.28 (m, 11H), 1.39–1.57 (m, 4H),1.72–1.85 (m, 2H), 2.16 (s, 3H), 2.24 (s, 2H), 3.40–3.50 (m, 2H),3.65–3.84 (m, 2H), 4.69 (dd, 2H), 5.36 (s, 1H), 6.71 (s, 1H), 6.76 (d,2H), 6.99 (t, 1H), 7.13 (d, 2H), 7.22–7.33 (m, 4H), 7.39 (s, 1H); m/z760.27

Example 1111,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(R)-N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was separated as by-product from the synthesis ofExample 108. NMR (500 MHz, CD₃OD) 0.78–0.85 (m, 6H), 1.02–1.60 (m, 12H),2.16 (d, 3H), 2.53 (d, 3H), 3.08–3.18 (m, 1H), 3.24 (s, 2H), 3.35 (v br,1H), 3.75 (v br, 2H), 4.62 (v br, 1H), 4.71 (dd, 2H), 5.60 (d, 1H), 7.71(s, 1H), 6.98 (t, 1H), 7.12 (d, 2H), 7.25–7.42 (m, 6H), 7.47 (d, 2H);m/z 772.25.

Example 1121,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N′-(3-methylthio-2-carboxypropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N′-(3-methylthio-2-methoxycarbonylpropyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 94; 68 mg, 0.087 mmol) in ethanol (5 ml) was added NaOH (9 mg in0.4 ml water) at 0° C. The reaction mixture was stirred at roomtemperature for 2.5 hours. Acetic acid was added and the solventevaporated under reduced pressure. The crude product was purified bypreparative HPLC using MeCN and ammonium acetate buffer (40:60 to 60:40)as eluent to give the title compound 52 mg (76%). NMR (500 MRz, CD₃OD)0.79–0.86 (m, 6H), 1.05–1.29 (m, 8H), 1.40–1.58 (m, 4H), 1.84–1.93 (m,4H), 2.01–2.21 (m, 5H), 2.26–2.34 (m, 1H), 3.26 (s, 2H), 3.76 (brs, 2H),4.52–4.58 (m, 1H), 4.70 (dd, 2H), 5.61 (s, 1H), 6.73 (s, 1H), 7.0 (t,1H), 7.14 (d, 2H), 7.27–7.43 (m, 6H), 7.49 (d, 2H); m/z 770.16.

Example 1131,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-[(S)-N′-(2-mercapto-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 106; 15 mg, 0.02 mmol) in methanol (1.5 ml) was added sodiummethoxide (0.104 mmol in 0.14 ml methanol) and methyl iodide (0.16 mmol)under nitrogen. The reaction mixture was stirred at room temperature for50 min. Acetic acid was added. The solvent was evaporated under reducedpressure and the residue was extracted with DCM/water. The organic layerwas separated washed with brine, dried and evaporated under reducedpressure to give the title compound 4 mg (26%). NMR (500 MHz, CD₃OD)0.75–8.30 (m, 6H), 1:03–1.57 (m, 12H), 2.10 (s, 3H), 2.17 (s, 3H),2.83–2.30 (m, 1H), 3.0–3.25 (m, 1H), 3.26 (s, 92H), 3.77 (brs, 2H),4.58–4.63 (m, 1H), 4.72 (dd, 2H), 5.64 (s, 1H), 6.72 (s, 1H), 7.0 (t,1H), 7.12 (d, 2H), 7.28–7.52 (m, 8H); m/z 756.25.

Example 1141,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-[N-{(R)-α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-[N-{(R)-α-[N′-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 102; 129 mg, 0.164 mmol) in DCM (5 ml) was added at 0° C. TFA(1.5 ml) under nitrogen. The reaction mixture was stirred at roomtemperature for 2 hours. The solvent was evaporated under reducedpressure and the crude product was purified by preparative HPLC usingMeCN and ammonium acetate buffer (40:60 to 50:50) as eluent to give thetitle compound 77 mg (63%). NMR (500 MHz, CD₃OD) 0.84 (t, 6H), 1.10–1.22(m, 8H), 1.35–1.45 (m, 4H), 2.34 (s, 3H), 3.19–3.27 (m, 2H), 3.55 (s,2H), 3.87 (dd, 2H), 4.67 (dd, 2H), 5.61 (s, 1H), 7.09–7.15 (m, 3H),7.27–7.37 (m, 6H), 7.47 (d, 2H); m/z 7.48.03 (M+NH₃).

Example 1151,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 118; 0.050 g, 0.105 mmol) in DMF (4 ml) was added2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid(Method 80; 0.037 g, 0.135 mmol) and N-methylmorpholine (0.040 ml, 0.363mmol). The mixture was stirred for 10 min and then was TBTU (0.044 g,0.137 mmol) added. The reaction mixture was stirred for two days beforethe solvent was removed under reduced pressure. The residue was purifiedby preparative HPLC using a MeCN/ammonium acetate buffer to give thetitle compound in 0.042 g (55%) as a white solid. NMR (DMSO-d₆)0.60–0.80 (m, 6H), 1.05–1.50 (m, 8H), 2.15 (s, 3H), 2.45–2.55 (m, 21H),3.05–3.80 (m, 6H), 4.70 (ABd, 1H), 4.80 (ABd, 1H), 5.25 (d, 1H),6.65–6.75 (m, 3H), 6.80–7.05 (m, 3H), 7.10–7.25 (m, 4H), 7.30 (s, 1H),8.20–8.30 (m, 1H). 8.45 (d, 1H).

Example 1161,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-[N-{(R)-α-[N′-(carboxymethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 118; 0.050 g, 0.105 mmol) in DCM (4 ml) was added(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 86; 0.036g, 0.136 mmol) and N-methylmorpholine (0.040 ml, 0.363 mmol). Themixture was stirred for 5 min and then was TBTU (0.044 g, 0.137 mmol)added. The reaction mixture was stirred for two days and then was TFA(1.5 ml) added. After 1.5 h, the solution was diluted with toluene;before the solvent was removed under reduced pressure. The residue waspurified by preparative HPLC using a MeCN/ammonium acetate buffer togive the title compound in 0.020 g (29%) as a white solid. NMR (DMSO-d₆)0.60–0.80 (m, 6H), 1.05–1.50 (m, 8H), 2.15 (s, 3H), 3.10–3.80 (m, 6H),4.70 (ABd, 1H), 4.85 (ABd, 1H), 5.60 (d, 1H), 6.70 (s, 1H), 6.80–7.05(m, 3H), 7.15–7.50 (m, 8H), 8.35 (brs, 1H), 8.55 (d, 1H).

Example 1171,1-Dioxo-3,3-dibutyl-5-phenyl-7methoxy-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 6; 0.020 g, 4.09*10⁻⁵ mol) in DMF (4 ml) was added2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid(Method 80; 0.014 g, 5.10*10⁻⁵ mol) and N-methylmorpholine (0.020 ml,1.81*10⁻⁴ mol). The mixture was stirred for 10 min and then was TBTU(0.016 g, 4.98*10⁻⁵ mol) added. The reaction mixture was stirred for 3 hand then the solvent was removed under reduced pressure. The residue waspurified by preparative HPLC using a MeCN/ammonium acetate buffer togive the title compound in 0.023 g (75%) as a white solid. NMR (500 MHz,DMSO-d₆) 0.65–0.80 (m, 6H), 0.80–1.50 (m, 12H), 2.40–2.60 (m, 2H),3.15–3.45 (m, 4H), 3.60 (s, 3H), 3.65 (brs, 2H), 4.60 (ABd, 1H), 4.70(ABd, 1H), 5.25 (d, 1H), 6.50 (s, 1H), 6.70–7.25 (m, 10H), 7.35 (s, 1H),8.20–8.30 (m, 1H). 8.50 (d, 1H), 9.40 (brs, 1H).

Example 1181,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-[N-{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 115; 0.020 g, 4.63*10⁻⁵ mol) in DMF (4 ml) was added2-{[(2R)-2-amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid(Method 80; 0.017 g, 6.20*10⁻⁵ mol) and N-methylmorpholine (0.016 ml,1.46*10⁻⁴ mol). The mixture was stirred for 10 min and then TBTU (0.019g, 5.92*10⁻⁵ mol) was added. The reaction mixture was stirred overnightand then the solvent was removed under reduced pressure. The residue waspurified by preparative HPLC using a MeCN/ammonium acetate buffer togive the title compound in 0.008 g (24%) as a white solid. NMR (500 MHz,DMSO-d₆) 0.65–0.80 (m, 6H), 0.80–1.60 (m, 8H), 2.40–2.55 (m, 2M),3.20–3.40 (m, 4H), 3.65 (brs, 2H), 4.65 (ABd, 1H), 4.70 (ABd, 1H), 5.25(d, 1H), 6.65–7.45 (m, 13H), 8.20–8.30 (m, 1H). 8.60 (d, 1H), 9.40 (brs,1H).

Example 1191,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-[N-α-(R)-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesized from1,1-oxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-[N-α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 45) by the procedure of Method 109. NMR (CD₃OD) 0.81 (brt, 6H),1.03–1.3 (m, 8H), 1.32–1.59 (m, 13H), 3.24 (brs, 2H), 3.57–3.77 (m, 2H),4.61 (brs, 2H), 5.51 (s, 1H), 6.83 (d, 1H), 7.0–7.1 (m, 3H), 7.26–7.43(m, 7H), 7.49 (d, 1H); m/z 708.5.

Example 1201,1-Dioxo-3,3-dibutyl-5-[4-(N′-t-butylureido)phenyl]-8-[N-α-(R)-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-(N′-t-butylureido)phenyl)-8-[N-α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 111; 30 mg, 0.042 mmol) was dissolved in THF (1.5 ml), H₂O (0.5ml) and LiOH (42 mg, 0.064 mmol, monohydrate) was added. The mixture wasstirred for 2 hours. The compound was purified by preparative HPLC usingan MeCN/ammonium acetate buffer gradient (5/95 to 100/0) as eluent togive the title product, 24 mg (82%). NMR (CD₃OD) 0.81 (brt, 6H),1.05–1.26 (m, 8H), 1.35 (s, 9H), 1.38–1.57 (m, 4H), 3.25 (brs, 2H),3.6–3.77 (m, 2H), 4.61 (ABq, 2H), 5.45 (s, 1H), 6.84 (d, 1H), 7.01–7.11(m, 3H), 7.24 (d, 2H), 7.26–7.37 (m, 3H), 7.37–7.42 (m, 2H), 7.50 (d,1H); m/z 707.5.

Preparation of Starting Materials

The starting materials for the Examples above are either commerciallyavailable or are readily prepared by standard methods from knownmaterials. For example, the following reactions are an illustration, butnot a limitation, of some of the starting materials used in the abovereactions.

Method 1

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-(ethoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium carbonate (0.30 g, 2.83 mmol), 2-bromopropanoic acid ethyl ester(0.145 g, 0.796 mmol) and tetrabutylammonium bromide (0.022 g, 0.07mmol) was added to a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051; 0.300 g, 0.663 mmol) in MeCN (10 ml). The suspension washeated under reflux overnight. The solvent was evaporated and the crudemixture was extracted (DCM/H₂O), dried. (MgSO₄), evaporated and purifiedby flash chromatography (Hex:EtOAc-5:1) to give the title compound 0.346g (95%) as a white solid. NMR 0.70–0.85 (m, 6H), 1.00–1.75 (m, 8H), 1.35(t, 3H), 1.70 (d, 3H), 3.05–3.25 (m, 2H), 3.55–3.90 (m, 2H), 4.20–4.35(m, 2H), 4.80 (q, 1H), 7.00–7.10 (m, 3H), 7.15 (s, 1H), 7.25–7.35 (m,2H), 7.45 (s, 1H).

Method 2

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-carboxyethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium hydroxide (0.045 g, 1.13 mmol) was added to a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1-(ethoxycarbonyl)ethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 1; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%) and heated underreflux. After 1.5 hours AcOH (0.2 ml) was added and most of the solventwas removed under reduced pressure. The crude product was extracted(DCM/H₂O), dried (MgSO₄) and evaporated to give the title compound 0.031g (65%) as white solid. NMR (500 MHz, CD₃OD) 0.70–0.85 (m, 6H),0.95–1.25 (m, 4H), 1.35–1.70 (m, 4H), 2.65 (d, 3H), 3.10–3.35 (m, 2H),3.45–3.95 (m, 2H), 4.70 (q, 1H), 6.90–7.35 (m, 6H), 7.45 (s, 1H).

Method 3

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-phenyl-1′-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

Ethyl α-bromophenylacetate (0.139 g), Na₂CO₃ (0.200 g) andtetrabutylammonium bromide (0.034 g) were added to a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051; 0.200 g, 0.442 mmol) in MeCN (6 ml). The suspension washeated under reflux overnight before the solvent was removed underreduced pressure. The crude product was extracted (DCM/H₂O) and purifiedby flash chromatography (Hex:EtOAc-5:1) to give the title compound 0.256g (94%) as a white solid. NMR 0.65–0.85 (m, 6H), 0.95–1.65 (m, 8H),3.00–3.15 (m, 2H), 3.50–3.80 (m, 2H), 3.70–3.80 (2s, 3H), 5.60 (s, 1H),5.65 (d, 1H) 7.00–7.60 (m, 17H), 8.05–8.20 (2d, 1H).

Method 4

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-phenyl-1′-carboxymethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

Lithium hydroxide (0.019 g) was added to a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[1′-phenyl-1′-ethoxycarbonylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 3; 0.244 g, 0.397 mmol) in THF/H₂O (2/1, 3 ml). After 2 days thesolvent was removed under reduced pressure and the crude mixture waspurified by HPLC to give the title compound 0.215 g (92%) as a whitesolid. NMR (CD₃OD) 0.60–0.80 (m, 6H), 0.90–1.25 (m, 4H), 1.30–1.60 (m,4H), 3.05–3.30 (m, 2H), 3.40–3.90 (m, 2H), 5.55 (s, 1H), 6.85–7.70 (m,12H).

Method 5

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Ethyl bromoacetate (0.13 ml), Na₂CO₃ (0.40 g) and tetrabutylammoniumbromide (0.030 g) were added to a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethylanalogue; 0.400 g, 0.927 mmol) in MeCN (10 ml). The suspension washeated under reflux overnight before most of the solvent was removedunder reduced pressure. The crude product was extracted (DCM/H₂O) andfiltered through a short silica-column (DCM:EtOAc-1:4) to give the titlecompound 0.476 g (99%). NMR 0.65–0.85 (m, 6H), 0.95–1.65 (m, 8H),3.00–3.15 (m, 2H), 3.50–3.80 (m, 2H), 3.70–3.80 (s, 3H), 5.60 (s, 1H),5.65 (d, 1H) 7.00–7.60 (m, 17H), 8.05–8.20 (d, 1H).

Method 6

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Lithium hydroxide (0.062 g) was added to a solution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 5; 0.448 g, 0.865 mmol) in THF/H₂O (2/1, 6 ml) After 1 hour AcOH(0.5 ml) was added and most of the solvent was removed under reducedpressure. The crude product was purified by HPLC (MeCN) to give thetitle compound 0.408 g (96%) as a white solid. NMR (CD₃OD) 0.75–0.85 (m,6H), 1.00–1.30 (m, 8H), 1.35–1.55 (m, 4H), 3.20 (s, 2H), 3.65 (s, 3H),3.70 (brs, 2H), 4.50 (s, 2H), 6.50 (s, 1H), 6.90–7.30 (m, 5H), 7.40 (s,1H).

Method 7

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 9616051; 1.0 g), ethyl bromoacetate (0.50 g), sodium carbonate (1.2g) and tetrabutylammonium bromide (60 mg) in MeCN (15 ml) were refluxedovernight. The solvent was removed under reduced pressure and theresidue was extracted (DCM/H₂O). The organic layer was separated and thesolvent was removed under reduced pressure. The residue purified bychromatography (DCM/EtOAc (90:10)) to give the title compound 1.2 g(98%). NMR (CD₃OD) 0.75–0.85 (m, 6H), 1.00–1.30 (m, 8H), 1.35–1.55 (m,4H), 3.20 (s, 2H), 3.65 (s, 3H), 3.70 (brs, 2H), 4.50 (s, 2H), 6.50 (s,1H), 6.90–7.30 (m, 5H), 7.40 (s, 1H).

Method 8

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A mixture of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051; 0.3 g), ethyl bromoacetate (0.14 g), sodium carbonate (0.3g), tetrabutylammonium bromide (0.02 g) in MeCN (10 ml) were refluxedfor 4 hours. The solvent was removed under reduced pressure. The residuewas partitioned, between DCM/H₂O and the organic layer was separated.The solvent was evaporated and the residue was purified bychromatography (DCM/EtOAc, 90:10) to give the title compound 0.34 g(95%). NMR (500 MHz) 0.7–0.9 (m, 6H), 1.0–1.8 (m, 11H), 3.2 (m, 2H),3.6–3.8 (brs, 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0–7.1 (m, 3H), 7.15 (s,1H), 7.3 (m, 2H), 7.4 (s, 1H).

Method 9

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 8; 0.34 g) and sodium hydroxide (0.3 g) were dissolved inethanol and the mixture was heated to reflux for 1 hour. Acetic acid (1ml) was added and the solvent was removed at reduced pressure. Theresidue was partitioned between DCM/H₂O and the organic layer wasseparated and dried. Trituration of the residue with n-hexane gave thetitle compound 0.29 g (90%) as a solid. NMR (500 MHz) 0.7–0.8 (m, 6H),1.0–1.7 (m, 8H), 3.1–3.2 (m, 2H), 3.6 (brs, 2H), 4.6 (s, 2H), 6.9–7.1(m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).

Method 10

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methoxy-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 7; 1.2 g) was dissolved in ethanol (20 ml). Sodium hydroxide(0.5) dissolved in H₂O (1 ml) was added and the reaction mixture waswarmed to 40° C. for 30 min. Acetic acid (1 ml) was added and thesolvent was removed at reduced pressure. The residue was partitionedbetween DCM/H₂O and the organic layer was separated and dried.Trituration of the residue with n-hexane gave the title compound 1.1 g(97%) as a solid. NMR 0.75–0.85 (m, 3H), 0.9 (t, 3H), 1.0–1.7 (m, 8H),3.2 (q, 2H), 3.65 (s, 3H), 3.65–3.85 (m, 2H), 4.7 (s, 2H), 6.4 (s, 1H),7.0 (t, 1H), 7.1 (d, 2H), 7.3 (t, 2H), 7.5 (s, 1H).

Method 11

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethylanalogue; 2.0 g, 4.16 mmol), ethyl bromoacetate (0.84 g, 5.03 mmol),sodium carbonate (2.0 g, 18.9 mmol) and tetrabutylammonium bromide (80mg, 0.25 mmol) were added to MeCN (20 ml). The mixture was refluxed for2 hours and then evaporated under reduced pressure. The residue wasextracted with DCM/water. The DCM layer was separated and evaporatedunder reduced pressure. The residue was purified by columnchromatography. The product was eluted with DCM/EtOAc (90:10) to givethe title compound 2.2 g (93%). NMR 0.7–0.8 (m, 6H), 1.0–1.6 (m, 15H),3.2 (brs, 2H), 3.7 (brs, 2H), 4.3 (q, 2H), 4.7 (s, 2H), 7.0–7.3 (m, 6H),7.4 (s, 1H).

Methods 12–13

The following compounds were synthesised by the procedure of Method 11using the appropriate acid and amine (source not indicated wherecommercially available).

Meth Compound M/z SM 12

538 Meth 83 13

538 Meth 84Method 14

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 11; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH(0.8 g in 1.5 ml water) was added to the solution and the mixture wasstirred for 30 min at room temperature. Acetic acid (2 ml) was added.The solvent was evaporated under reduced pressure and the residue wasextracted with EtOAc/water. The EtOAc layer was separated, dried andevaporated under reduced pressure to give the title compound 2.0 g(95%). NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.5 (m, 12H), 3.2 (brs, 2H),3.7 (brs, 2H), 4.7 (s, 2H), 7.0–7.3 (m, 6H), 7.4 (s, 1H).

Method 15

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-isopropoxy-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To isopropyl alcohol (12 ml) was added sodium (115 mg, 5 mmol) and thetemperature was then raised to 80° C. to let the alcohol salt form.After all the sodium was dissolved1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 9; 100 mg, 0.2 mmol) was added in one portion. The reaction wasthen refluxed overnight, and then cooled to room temperature andquenched with acetic acid. The solvent was then removed under reducedpressure and the residue was dissolved in water and MeCN (70/30) andpartially purified by HPLC. The residue was dissolved in ethylene glycoland NaOH (500 mg) was added. This reaction mixture was heated to 125° C.overnight and then cooled to room temperature and quenched with aceticacid, and EtOAc (100 ml) was added. The ethylene glycol was removed bywashing the organic layer with acidic water three times. The organiclayer was then concentrated and the residue was purified again as aboveto give the title compound 40 mg (41%). NMR (300 MHz) 0.7–1.0 (m, 6H),1.0–1.8 (m, 15H), 3.2 (q, 2H), 3.75 (m, 2H), 4.3 (m, 1H), 4.6 (s, 2H),6.35 (s, 1H), 6.95–7.2 (m, 3H), 7.2–7.4 (m, 2H), 7.55 (s, 1H).

Method 16

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxcarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 25; 500 mg, 1.2 mmol) was added MeCN (30 ml), tetrabutylammoniumbromide (30 mg, 0.08 mmol), anhydrous sodium carbonate (500 mg, 4.7mmol), ethyl bromoacetate (0.14 ml, 1.26 mmol) and caesium carbonate (20mg, 0.06 mmol). This reaction mixture was then stirred overnight at 80°C. Then the solvent was removed under reduced pressure, water and DCMwere added and the aqueous phase was extracted three times with DCM. Thecombined organic phases were then dried, concentrated and purified byflash chromatography [DCM:EtOAc, 1:0, 9:1] to give the title compound600 mg (99%). NMR (300 MHz) 0.8–1.0 (m, 6H), 1.0–1.8 (m, 11H), 2.2 (s,3H), 3.2 (q, 2H) 3.75 (brq, 2H), 4.3 (q, 2H), 4.75 (s, 1H), 6.7 (s, 1H),6.95 (t, 1H), 7.05 (d, 2H), 7.25 (t, 2H), 7.3 (s, 1H).

Method 17

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 16; 478 mg, 0.95 mmol) was added THF (15 ml), water (3 ml) andLiOH (34 mg, 1.4 mmol). The reaction was then stirred for 1 hour. Thenacetic acid (0.2 ml) was added along with water (10 ml) and DCM (10 ml)The aqueous layer were then extracted three times with DCM. The combinedorganic phases were then dried and concentrated to give the titlecompound 450 mg (99%). NMR 0.7–0.9 (m, 6H), 1.0–1.7 (m, 8H), 2.2 (s,3H), 3.2 (q, 2H), 3.7 (m, 2H), 4.8 (s, 2H), 6.65 (s, 1H), 6.95 (t, 1H),7.05 (d, 2H), 7.25 (t, 2H), 7.35 (s, 1H), 8.4 (brs, 1H).

Method 18–19

The following compounds were synthesised by the procedure of Method 17using the appropriate acid and amine (source not indicated wherecommercially available) except two equivalents of LiOH was used and theextraction was performed after 2 hours reaction time using EtOAc.

Meth Compound M/z SM 18

510 Meth 12 19

510 Meth 13Method 20

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 16; 122 mg, 0.24 mmol) was added DCM (3 ml), water (3 ml) andpotassium carbonate (120 mg, 0.87 mmol). The reaction mixture was thencooled to 0° C. and m-chloroperoxybenzoic acid (160 mg, 0.51 mmol) wasadded in one portion. After 5 hours the reaction was quenched with DCMand saturated sodium hydrogen carbonate solution the aqueous phase werethen extracted three times with DCM. The combined organic phases weredried, concentrated and purified by flash chromatography [DCM:EtOAc,9:1] to give the title compound 46 mg (35%). NMR 0.7–0.8 (m, 6H),1.0–1.65 (m, 11H), 3.2 (q, 2H), 3.3 (s, 3H), 3.7 (brs, 1H), 4.25 (q,2H), 4.8 (s, 2H), 7.0–7.1 (m, 3H), 7.2–7.3 (m, 2H), 7.5 (s, 2H).

Method 21

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-mesyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 20; 46 mg, 0.085 mmol) was added THF (5 ml), water (1 ml) andLiOH (10 mg, 0.4 mmol). The reaction was stirred for 1 hour and thenexcess acetic acid was added to quench the reaction. Water and DCM wereadded and the aqueous phase was extracted three times with DCM. Thecombined organic phases were dried and concentrated to give the titlecompound 40 mg (91%). NMR 0.7–0.85 (m, 6H), 1.0–1.7 (m, 8H), 3.2 (m,2H), 3.3 (s, 3H), 3.8 (s, 2H), 4.9 (s, 2H), 5.0 (brs, 1H), 7.05–7.15 (m,3H), 7.3–7.4 (t, 2H), 7.5 (s; 1H), 7.6 (s, 1H).

Method 22 (Preparation 1)

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 14; 500 mg, 0.93 mmol) was dissolved in DMF (10 ml). Sodiummethanethiolate (200 mg, 2.85 mmol) was added and the mixture wasstirred for 2 hours at 50° C. Acetic acid (0.4 ml) was added and thesolvent was evaporated under reduced pressure. The residue was extractedwith EtOAc/water. The EtOAc layer was separated, dried and evaporatedunder reduced pressure to give, the title compound 450 mg (96%). NMR.(300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.2 (s, 2H), 3.2 (brs, 2H),3.7 (brs, 2H), 4.8 (s, 2H), 6.6 (s, 1H), 6.9–7.1 (m, 3H), 7.2–7.4 (m,3H).

Method 22 (Preparation 2)

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A solution of NaOH (4.67 g, 116 mmol) in water (10 ml) was added to asolution of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 114; 15.45 g, 28.71 mmol) in EtOH (160 ml). The solution wasstirred for 30 min at room temperature. The solvent was removed underreduced pressure and the residue was partitioned between EtOAc and 1.0 MHCl. The aqueous layer was extracted twice more with EtOAc and thecombined organic extracts were washed with brine and concentrated togive the title compound (14.28 g, 98%) as a white powder. NMR (500 MHz,DMSO-d₆) 0.65–0.80 (m, 6H), 0.90–1.50 (m, 12M), 2.20 (s, 3H), 3.25 (s,2H), 3.65 (bs, 2H), 4.80 (s, 2H), 6.70 (s, 1H), 6.80–7.30 (m, 6H), 13.20(s, 1H).

Method 23–24

The following compounds were synthesised by the procedure of Method 22(Preparation 1), using the appropriate acid and amine (source notindicated where commercially available) except that the reactions wereperformed at ambient temperature and in Method 24 for extended reactiontime.

Meth Compound M/z SM 23

478 Meth 18 24

478 Meth 19Method 25

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO9616051; 600 mg, 1.29 mmol) were added DMF (5 ml) and sodiummethanethiolate (450 mg, 6.42 mmol). The reaction was then heated to 60°C. for 1 hour. The oil bath was then heated to 120° C. for 4 hours. Toquench the reaction, the temperature was lowered to room temperature andexcess acetic acid was added quickly. The reaction was kept under a flowof nitrogen through sodium hypochlorite for 2 hours. Water and EtOAcwere added and the aqueous phase was extracted three times with EtOAc.The combined organic phases were washed with water, dried andconcentrated under reduced pressure. The residue was then purified byflash chromatography [DCM:EtOAc, 9:1] to give the title compound 0.5 g(92%). NMR 0.65–0.8 (m, 6H), 0.95–1.6 (m, 8h), 3.1 (q, 2H), 3.6 (brq,2H), 6.75 (s, 1H), 6.8 (t, 1H), 6.9 (d, 2H), 7.15 (t, 2H), 7.55 (s, 1H).

Method 26

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(synthesised by the of WO9616051 for the corresponding 3-butyl-3-ethylanalogue; 40 mg, 0.08 mmol) was added DMF (2 ml), sodium methanethiolate(60 mg, 0.85 mmol) and sodium borohydride (60 mg, 1.6 mmol). Thereaction was run overnight at 60° C. Additional sodium borohydride (60mg, 1.6 mmol) and sodium methanethiolate (60 mg, 0.85 mmol) was addedand the temperature was raised to 120° C. The reaction heated at thistemperature for 4 hours and then cooled to room temperature. Then aceticacid was added under a flow of nitrogen, through sodium hypochloriteovernight. Water and EtOAc was added and the aqueous phase was extractedthree times with EtOAc. The combined organic phases were washed with HCl(1M), dried and concentrated under reduced pressure. The residue wasthen purified by flash chromatography [EtOAc:heptane, 1:4] to give thetitle compound 0.34 g (93%). NMR 0.7–0.9 (m, 6H), 1.0–1.6 (m, 12H), 2.2(s, 3H), 3.1 (s, 2H), 3.4 (s, 2H), 3.7 (brs, 2H), 6.7 (s, 1H), 6.85–7.05(m, 2H), 7.2–7.4 (m, 2H).

Method 27

2-[(2′R)-2′-(t-Butoxycarbonylamino)-2′-phenylethanoylamino]ethanesulphonicacid ammonium salt

2-Aminoethanesulphonic acid (740 mg, 5.91 mmol) and(2R)-2-(t-butoxycarbonylamino)-2-phenylacetic acid (1.09 g, 4.34 mmol)were dissolved in DMF (20 ml). DIPEA (2.8 ml, 16.1 mmol) and TBTU (1.53g, 4.78 mmol) were added and the mixture was stirred for 2 hours at 60°C. The solvent was evaporated at reduced pressure. The residue waspurified by preparative HPLC using an MeCN/ammonium acetate buffergradient (5/95 to 100/0) as eluent to give the title compound 589 mg(32%). NMR (CD₃OD) 1.43 (s, 9H), 2.85–3.0 (m, 2H), 3.53–3.68 (m, 2H),5.1 (brs, 1H), 7.25–7.45 (m, 5H).

Method 28

2-((2′R)-2′-amino-2′-phenylethanoylamino)ethanesulphonic acid ammoniumsalt

2-[(2′R)-2′-(t-Butoxycarbonylamino)-2′phenylethanoylamino]ethanesulphoricacid ammonium salt (Method 27; 589 mg, 1.57 mmol) was dissolved in EtOAc(20 ml) and the mixture was cooled in an ice bath. Hydrogen chloride gaswas bubbled through the reaction, the ice bath was removed and thereaction was allowed to stand for 30 minutes at room temperature. Thesolvent was evaporated at reduced pressure. The residue was thenredissolved in EtOAc (20 ml) and cooled in an ice bath. Hydrogenchloride gas was again bubbled through the reaction, the ice bath wasremoved and the reaction was allowed to stand for 30 minutes at roomtemperature. The solvent was evaporated at reduced pressure. DIPEA inDCM was added and the mixture was evaporated at reduced pressure. Thiswas repeated twice. The mixture was lyophilised to give the titlecompound 563 mg (85%) containing 1 equivalent ofdi-isopropylethylammoniumchloride. NMR (D₂O) 1.35–1.38 (m, 15H),2.96–3.12 (m, 2H), 3.21 (q, 2H), 3.50–3.80 (m, 4H), 5.11 (brs, 1H),7.45–7.55 (m, 5H).

Method 29

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 22; 250 mg, 0.49 mmol), (R)-2-phenylglycine methyl esterhydrochloride (120 mg, 0.60 mmol) and DIPEA (300 mg, 2.3 mmol) weredissolved in DCM (10 ml) and the mixture was stirred for 5 min in roomtemperature. TBTU (210 mg. 0.65 mmol) was added and the mixture wasstirred for 30 min at room temperature. The solvent was evaporated underreduced pressure and the residue was placed on a column and the productwas eluted with DCM/EtOAc (90:10) to give the title compound 306 mg(95%). NMR (500 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 12H), 2.1 (s, 3H) 3.2brs, 2H), 3.6–3.8 (m, 5H), 4.6 (ABq, 2H, 5.6 (d, 1H), 6.6 (s, 1H),6.9–7.5 (m, 11H), 7.9 (d, 1H).

Methods 30–45

The following compounds were synthesised by the procedure of Method 29using the appropriate acid and amine (source not indicated wherecommercially available) except that the reaction time was extended to 2hours for some methods.

Meth Compound NMR or m/z SM 30

(300MHz, CD₃OD)0.8–0.9(m,6H), 1.1–1.6(m, 12H), 2.2(s,3H), 3.3(s, 2H),3.75(brs, 5H),4.7–4.8(m, 2H), 5.45(s, 1H),6.7(s, 1H), 6.8–7.3(m,9H),7.45(s, 1H) Meth 22 31

(300MHz, CD₃OD)0.75–0.95(m, 6H), 1.0–1-6(m, 12H), 2.1(s, 3H), 3.2(s,2H), 3.7(s, 5H),4.65(s, 2H), 5.85(s, 1H), 6.7(s,1H), 6.9–7.4(m, 9H) Meth22 32

(300MHz, CD₃OD)0.75–0.9(m, 6H), 1.0–1.6(m, 12H), 2.2(s, 3H), 3.2(s, 2H),3.75(s, 5H),4.7(brs, 2H), 5.7(s, 1H), 6.7(s,1H), 6.9–7.4(m, 6H),7.55–7.8(m, 4H) Meth 22andMeth 71 33

0.70–0.85(m, 6H), 0.95–1.75(m,8H), 1.55–1.75(2d, 3H), 3.05–3.30(m, 2H),3.55–3.90(m, 2H),3.70–3.80(2s, 3H)4.75–4.90(2q, 1H), 5.60(d, 1H),7.00–7.55(m, 12H), 7.80–7.95(m, 1H) Meth 2 34

0.65–0.85(m, 6H), 0.95–1.65(m, 8H), 3.00–3.15(m, 2H),3.50–3.80(m, 2H),3.70–3.80(2s, 3H), 5.60(s, 1H), 5.65(d,1H)7.00–7.60(m, 17H),8.05–8.20(2d, 1H) Meth 4 35

(CD₃OD)0.75–0.85(m, 6H),1.00–1.30(m, 8H), 1.35–1.55(m,4H), 3.20(s, 2H),3.55(s, 3H),3.70(s, 3H), 3.75(brs, 2H), 4.60(ABq, 2H), 5.55(s, 1H),6.50(s,1H), 6.95–7.40(m, 10H), 7.50(s, 1H) Meth 6 36

707.4 Ex 12 37

0.75–0.85(m, 6H), 1.00–1.60(m, 12H), 3.20(s, 2H), 3.60(s,3H), 3.75(brs,2H), 3.75(s, 3H),4.55(ABq, 2H), 5.85(d, 1H),6.40(s, 1H), 6.95–7.45(m,9H),7.55(s, 1H), 8.05(d, 1H) Meth 6 38

0.75–0.85(m, 6H), 1.00–1.60(m,12H), 2.20(s, 3H), 3.20(s, 2H),3.75(brs,2H), 3.80(s, 3H), 4.60(ABq, 2H), 5.90(d, 1H), 6.65(s,1H), 6.95–7.45(m,10H), 7.95(d, 1H) Meth 22 39

(500MHz)0.7–0.8(m, 6H), 1.0–1.5(m, 12H), 3.2(m, 2H), 3.7–3.8(m, 5H),4.6(ABq, 2H), 5.6(d, 1H), 6.8–7.4(m, 10H), 7.5(s,1H) Meth 14 40

(300MHz)0.7–0.8(m, 6H), 1.0–1.6(m, 12H), 3.2(brs, 2H), 3.7–3.8(m, 5H),4.6(ABq, 2H), 5.6(d, 1H), 6.8(d, 2H), 7.0–7.4(m,8H), 7.9(d, 1H) Meth 1441

766.4(M-(t-butyl)+2H) Ex 12 42

739.3 Ex 38 43

667 Meth 22 44

724 Ex 18 45

722.5 Meth 109Method 46

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-[N-((S)-1′-phenyl-1′-methoxycarbonylmethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-8-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 9; 50 mg, 0.098 mmol) was dissolved in DCM (2 ml). Methyl(2S)-amino(phenyl)acetate (19 mg, 0.12 mmol) and DIPEA (0.068 ml, 0.39mmol) were added and the reaction was stirred for 2 minutes. TBTU (42mg, 0.13 mmol) was added and the mixture was stirred for 1.5 hours atroom temperature. The mixture was put on a pre-packed ISOLUTE column andeluted with 10 ml DCM/EtOAc 8/2 to give the title compound 60 mg (93%).M/z 657.5.

Methods 47–62

The following compounds were synthesised by the procedure of Method 46(except that the reaction times were overnight) using the appropriateacid and amine (source not indicated where commercially available).

Meth Compound NMR or M/z SM 47

609.4 Meth 10 48

625.4 Meth 17 49

685.3 Meth 14 50

609.4 Meth 10 51

637.4 Meth 15 52

657.4 Meth 21 53

685.3 Meth 14 54

0.73–0.95(m, 6H), 0.98–1.78(m,8H), 3.12–3.28(m, 2H), 3.6–4.0(m,5H),4.60(ABq, 2H), 5.79(d, 1H),6.0(brs, 1H), 6.54(dd, 1H), 6.83(t,1H),6.95(dd, 1H), 7.0–7.5(m, 7H),8.43(d, NH), 9.32(brs, 1H) Meth 9andMeth 7455

0.75–0.9(m, 6H), 1.0–1.78(m, 8H),3.10–3.26(m, 2H), 3.63–3.87(m,8H),4.56(ABq, 2H), 5.76(d, 1H),5.99(brs, 1H), 6.38(s, 1H), 6.51(dd,1H),6.81(t, 1H), 6.93(dd, 1H), 7.0–7.15(m, 3H), 7.23–7.4(m, 2H), 7.55(s,1H), 8.54(d, NH), 9.45(brs, 1H) Meth 10andMeth 74 56

0.76–0.87(m, 6H), 1.0–1.8(m, 8H),2.23(s, 3H), 3.1–3.25(m, 2H),3.6–3.95(m, 5H), 4.61(ABq, 2H), 5.79(d, 1H), 6.0(brs, 1H), 6.54(dd,1H),6.65(s, 1H), 6.83(t, 1H), 6.92–7.1(m, 4H), 7.23–7.4(m, 3H),8.37(d,NH), 9.35(brs, 1H) Meth 17andMeth 74 57

(CD₃OD)0.76–0.85(m, 6H), 1.02–1.3(m, 8H), 1.36–1.56(m, 4H), 2.16(s, 3H),3.24(brs, 2H), 3.66–3.80(m,5H), 4.71(ABq, 2H), 5.57(s, 1H),6.71(s, 1H),6.98(t, 1H), 7.06–7.14(m, 4H), 7.28(brt, 2H), 7.37–7.45(m, 3H) Meth22andMeth 75 58

(CD₃OD)0.76–0.85(m, 6H), 1.02–1.28(m, 8H), 1.36–1.56(m, 4H),1.96(s, 3H),3.24(brs, 2H), 3.6–3.8(m, 5H), 4.73(ABq, 2H), 5.76(s,1H), 6.63(s, 1H),6.94–7.04(m, 2H),7.07–7.15(m, 3H), 7.27(t, 2H), 7.31(s, 1H), 7.37(d,1H), 7.42(s, 1H),7.56(d, 1H) Meth 22 59

(CD₃OD)0.80(brt, 6H), 1.0–1.28(m, 8H), 1.36–1.54(m, 4H), 3.22(brs, 2H),3.61(s, 3H), 3.69–3.8(m, 5H), 4.62(ABq, 2H), 5.56(s,1H), 6.49(s, 1H),6.99(brt, 1H),7.07–7.16(m, 4H), 7.29(brt, 2H),7.37–7.43(m, 2H), 7.52(s,1H) Meth 6andMeth 75 60

(CD₃OD)0.75–0.84(m, 6H), 1.0–1.29(m, 8H), 1.35–1.54(m, 4H),3.20–3.23(m,5H), 3.65–3.8(m,5H), 4.64(ABq, 2H), 5.74(s, 1H),6.34(s, 1H),6.95–7.04(m, 2H),7.09–7.15(m, 3H), 7.24–7.31(m,3H), 7.37(d, 1H),7.50–7.54(m, 2H) Meth 6 61¹

0.74–0.83(m, 6H), 0.98–1.7(m,8H), 3.18(ABq, 2H), 3.60–3.90(m,5H),4.59(ABq, 2H), 5.67(d, 1H),7.0–7.2(m, 4H), 7.2–7.55(m, 8H),7.91(d, NH)Meth 9 62

639.4 Meth 17andMeth 76 ¹Eluent was DCM/EtOAc in a stepwise gradientfrom 100/0, 9/1, 8/2Method 63

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-1′-phenyl-1′-[N′-(t-butoxycarbonylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine.

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 1; 110 mg, 0.17 mmol), glycine tert-butyl ester (30 mg, 0.23mmol) and DIPEA (120 mg, 0.93 mmol) were dissolved in DCM (2 ml). Themixture was stirred for 5 mins at room temperature. TBTU (72 mg, 0.22mmol) was added and the mixture was stirred for 1 h at room temperature.The solvent was evaporated at reduced pressure and the residue wasplaced on a column and the product was eluted with DCM/EtOAc (90:10) togive the title compound 122 mg (94%). NMR (300 MHz) 0.7–0.8 (m, 6H),1.0–1.6 (m, 21H), 2.2 (s, 3H) 3.2 (s, 2H), 3.7–4.0 (m, 4H), 4.6 (ABq,2H), 5.6 (d, 1H), 6.4 (t, 1H), 6.6 (s, 1H), 6.9–7.5 (m, 11H), 8.1 (d,1H).

Methods 64–69

The following compounds were synthesised by the procedure of Method 63using the appropriate acid and amine (source not indicated wherecommercially available).

Meth Compound NMR or M/z SM 64

756.1 Ex 22 65

(CD₃OD)0.75–0.85(m, 6H), 1.1–1.3(m, 8H), 1.4(s, 9H), 1.45–1.55(m, 4H),2.15(s, 3H), 3.25(s, 2H),3.75(brs, 1H), 3.85(s, 2H), 4.7(ABq, 2H),5.5(s, 1H), 6.7(s,1H), 6.75–7.35(m, 9H), 7.4(s,1H) Ex 2 66

937.9(M−H)⁻ Ex 2 67

796.4 Ex 1 68

Ex 1 69

Ex 1Method 70

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-{N-[(S)-1′-phenyl-1′-(diethoxyphosphoryl)methyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesised from1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 9) and diethyl (S)-amino(phenyl)methylphosphonate by theprocedure of Example 33. NMR (600 MHz) 7.77–7.72 (1H, m), 7.47–7.42 (3H,m), 7.36–7.27 (5H, m), 7.14 (1H, s), 7.10–7.03 (2H, m), 5.55–5.48 (1H,m), 4.63–4.51 (2H, m), 4.14–4.02 (2H, m), 3.99–3.92 (1H, m), 3.81–3.60(3H, m), 3.22–3.10 (2H, m), 1.65–1.25 (8H, m), 1.19–0.95 (6H, m),0.78–0.73 (6H, m).

Method 71

4-Trifluoromethyl-α-methoxycarbonylbenzylamine

4-Trifluoromethyl-α-carboxybenzylamine (1.4 g, 1.83 mmol) andthionylchloride were added to methanol (8 ml) and the mixture wasrefluxed for 2 h. The solvent was evaporated under reduced pressure. Theresidue was suspended in diethyl ether and the product was filtered off,washed with ether and dried to give the title compound 0.34 g (69%).

NMR (300 MHz, DMSO-d₆) 3.3 (s, 1H), 5.45 (s, 1H), 7.7–7.9 (m, 4H), 9.25(brs, 3H).

Method 72

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-1′-phenyl-1′-[N-(ethoxycarbonylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Example 38; 52 mg, 0.082 mmol) and glycine ethyl ester hydrochloride(18 mg, 0.129 mmol) were dissolved in DCM (2 ml) and DIPEA (0.70 ml,0.42 mmol) was added. After stirring at ambient temperature for 5 minTBTU (34 mg, 0.11 mmol) was added and the mixture was stirred for 2hours. The solvent was evaporated and the residue was purified withflash chromatography (DCM:EtOAc 10:3) to give the title compound 50 mg(88%). NMR (500 MHz) 0.86 (m, 6H), 1.10–1.75 (m, 8H), 1.28 (m, 3H), 2.23(s, 3H), 3.19 (q, 2H), 3.75 (m, 2H), 3.99–4.25 (m, 4H), 4.64 (q, 2H),5.64 (m, 1H), 6.35 (brs, 1H), 6.69 (s, 1H), 7.03 (t, 1H), 7.09 (d, 1H),7.29–7.52 (m, 7H), 8.10 (d, 1H).

Method 73

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-1′-phenyl-1′-[N-(1″-methoxycarbonyl-1″-phenylmethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesised by the procedure of Method 72 using1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-((R)-1′-phenyl-1′-carboxymethyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 38)and methyl (2R)-amino(phenyl)acetate hydrochloride.

Method 74

1-(1′-Methoxycarbonyl-1′-aminomethyl)-2,3-dihydroxyphenyl hydrochloridesalt

1-(1′-Carboxy-1′-aminomethyl)-2,3-dihydroxyphenyl (40 g, 0.218 mmol) wasmixed with methanol (230 ml). HCl gas was bubbled through. The mixturewas refluxed for 2 hours. The solvent was evaporated under reducedpressure. The product was crystallised from methanol/EtOAc/diethyl etherto yield 35.5 g (70%) of the title product. NMR (600 MHz, CD₃OD) 3.76(s, 3H), 5.19 (s, 1H), 6.68–6–75 (m, 2H), 6.85 (dd, 1H)

Method 75

(R)-1-(1′-Methoxycarbonyl-1′-aminomethyl)-4-fluorophenyl hydrochloridesalt

(2R)-amino(4-fluorophenyl)acetic acid (570 mg, 2.77 mmol) was dissolvedin methanol (5 ml) and cooled in an ice-bath. Thionyl chloride (2 ml)was added dropwise and temperature was allowed to reach roomtemperature. After 5 hours the mixture was evaporated under reducedpressure. The procedure was repeated and the reaction was stirredovernight. The mixture was evaporated under reduced pressure to give thetitle product in a quantitative yield. NMR (500 MHz, CD₃OD) 3.84 (s,3H), 5.26 (s, 1H), 7.26 (t, 2H), 7.53 (dd, 2H).

Methods 76–77

The following compounds were synthesised by the procedure of Method 75using the appropriate acid and amine (source not indicated wherecommercially available).

Meth Compound NMR SM 76 (S)-α-Methylamino- (CD₃OD)2.63(s, 3H), 3.81(S)-α- α-methoxycarbonyl- (s, 3H), 5.15(s, 1H), Methylamino- benzyl7.45–7.55(m, 5H) α-carboxy- benzyl 77¹ α-Methoxy- (D₂O)2.65(s, 3H), 3.81(methylamino) carbonyl-N-methyl- (s, 3H), 5.15(s, 1H), (phenyl)aceticbenzylamine 7.45–7.48(m, 2H), acid hydrochloride 7.52–7.59(m, 3H) ¹Totalreaction time 5 daysMethod 78

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N-[(R)-α-(t-butoxycarbonyl)-4hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine

tert-Butyl (2R)-amino(4-hydroxyphenyl)acetate (104 mg, 0.47 mmol) and1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 17; 185 mg, 0.39 mmol) were dissolved in DCM (5 ml) and lutidine(0.09 ml, 0.77 mmol) was added. After stirring at room temperature for 5min o-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (208 mg, 0.55 mmol) was added and the reactionmixture was stirred at room temperature for 2 hours. Purification withflash chromatography (DCM:EtOAc 10:1→5:1) gave the title compound (175mg, 66%). NMR (300 MHz) 0.81 (m, 6H), 1.05–1.65 (m, 8H), 1.42 (s, 9H),2.21 (s, 3H), 3.17 (ABq, 2H), 3.74 (m, 2H), 4.60 (ABq, 2H), 5.22 (brs,1H), 5.49 (d, 1H), 6.67 (s, 1H), 6.79 (m, 2H), 7.00 (t, 1H), 7.07 (d,2H), 7.23–7.30 (m, 3H), 7.40 (s, 1H), 7.82 (brd, 1H).

Method 79

The following compounds were synthesised by the procedure of Method 78using the appropriate starting material.

Meth Compound M/z SM 79

639.3 Meth 17 andMeth 77Method 80

2-{[(2R)-2-Amino-2-(4-hydroxyphenyl)ethanoyl]amino}ethanesulphonic acid

N-Boc-4-hydroxyphenylglycine (1.00 g, 3.21 mmol) was dissolved in DMF (5ml) and tetrabutylammonium taurine (2.36 g, 6.42 mmol) was addedtogether with additionally 5 ml DMF. The resulting suspension was cooledon ice and TBTU (1.24 g, 3.85 mmol) was added. The ice bath was removedafter 30 min and the mixture was stirred for 2 hours before it wasfiltered and concentrated. TFA in DCM (20%, 20 ml) was added and thereaction mixture was stirred overnight. Ethanol (20 ml) was added andthe solvents evaporated. The crude product was refluxed in ethanol (100ml) for 1 hour. Filtration yielded the pure title compound as a whitesolid, 626 mg (71%). NMR (DMSO-d₆) 2.4–2.6 (m, 2H), 3.2–3.4 (m, 2H),4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t, 1H), 8.4 (brs, 3H),9.7 (s, 1H).

Method 81

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-carboxymethylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(113 mg, 0.24 mmol), Cs₂CO₃ (170 mg, 0.52 mmol) and ethyl thioglycolate(0.060 ml, 0.54 mmol) in DMF (4.0 ml) were subjected to microwaveirradiation in a Smith Synthesiser at 80° C. for 3 min and then at 90°C. for 8 min. The reaction mixture was diluted with water (250 ml) andextracted with DCM (5×10 ml) and collected organic layers were dried(MgSO₄), concentrated and purified on a short column (petroleum ether:EtOAc 4:1→2:1). The resulting product was dissolved in THF (2 ml) andwater (2 ml) and NaOH (aq., 0.5 ml, 1 M) was added and the reactionmixture was stirred at room temperature for 2 hours. The reaction wasquenched with HCl (1 M) and the reaction mixture was diluted with water(10 ml) and extracted with DCM (3×3 ml). Purification with preparativeHPLC yielded the title compound (58 mg, 59%). NMR (300 MHz, CD₃OD) 0.81(m, 6H), 1.00–1.70 (m, 8H), 3.21 (m, 2H), 3.42 (m, 2H), 3.71 (m, 2H),3.92 (s, 3H), 6.88 (m, 2H), 7.02 (m, 2H), 7.23 (t, 2H), 7.40 (s, 1H).

Method 82

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-ethoxycarbonylmethylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 9; 50 mg, 0.098 mmol) and Cs₂CO₃ (51 mg, 0.15 mmol) were addedto DMF (2.0 ml) and ethyl thioglycolate (0.02 ml, 0.15 mmol) was added.The reaction mixture was subjected to microwave irradiation in a SmithSynthesiser at 150° C. for 5 min. The reaction mixture was diluted withwater (100 ml), made acidic with HCl (1 M), extracted with DCM (3×10 ml)and the collected organic layers were dried (MgSO₄) to give the crudetitle compound (54 mg). M/z 550.2.

Method 83 and Method 84

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Enantiomer 1); and1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Enantiomer 2)

The two enantiomers of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051) were obtained by separation of the corresponding racemicmixture using preparative HPLC. The column used was a Chiralpak AD(20×250 mm i.d., 10□m) and the mobile phase was a heptane/IPA mixture inratio 90/10. The injected racemate (17.3 mg in IPA (1 ml)) was elutedwith a flow of 10 ml/min and the chromatogram was followed withUV-detection at 285 nm. Totally 260 mg racemate was separated yielding121 mg of the first eluting enantiomer (Enantiomer 1) and 115 mg of thesecond eluting enantiomer (Enantiomer 2). Total yield 91%. Each of thetwo enantiomers was obtained in 99.4% e.e.

Method 85

(R)-N-Benzyloxycarbonyl-α-[N′-(t-butoxycarbonylmethyl)carbamoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-carboxybenzylamine (10 g, 35.0 mmol) andt-butylglycine hydrochloride (6.3 g, 37.4 mmol) was dissolved in DCM(200 ml) with 2,6-lutidine (8.2 ml, 70.4 mmol). After stirring 5 min at0° C. TBTU (12.4 g, 38.6 mmol) was added and stirring was continued 1hour 30 min at 0° C. and 3 hours 45 min at room temperature. Thereaction mixture was washed with water (2×100 ml), dried (MgSO₄) andpurified with flash chromatography (DCM:EtOAc 7:1→5:1) to give the titlecompound (13 g, 94%). NMR (500 MHz) 1.45 (s, 9H), 3.84 (d, 1H), 4.00(dd, 1H), 5.10 (m, 2H), 5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H),7.30–7.44 (m, 10H).

Method 86

(R)-α-[N-(t-Butoxycarbonylmethyl)carbamoyl]benzylamine

(R)-N-Benzyloxycarbonyl-α-[N′-(t-Butoxycarbonylmethyl)carbamoyl]benzylamine(Method 85; 12.8 g, 32.2 mmol) was dissolved in EtOH (99%, 200 ml) andtoluene (50 ml). Pd/C (10%, 0.65 g) was added and hydrogenation wasperformed at atmospheric pressure for 5 hours 30 min at roomtemperature. The reaction mixture was filtered through diatomaceousearth and the solvents were evaporated to give the title compound (8.4g, 99%). NMR (600 MHz) 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H),7.31–7.42 (m, 5H), 7.51 (brs, 1H).

Method 87

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-α-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 22; 50 mg, 0.099 mmol) was dissolved in DCM (2 ml).(S)-Phenylglycine methyl ester hydrochloride (24.8 mg, 0.123 mmol) anddiisopropyl ethyl amine (70 □l, 0.401 mmol) were added. The mixture wasstirred for 15 min and then TBTU (38 mg, 0.118 mmol) was added. Thereaction was completed after 1.5 h (LC/MS). The crude product waspurified by flash chromatography using chloroform/EtOAc (8/2) as theeluent (88.6%; 55.2 mg, 0.064 mmol). M/z 653.

Method 88

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-{(S)-α-[N′-(methoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-(S)-(α-carboxybenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Example 88; 25mg, 0.039 mmol) and glycine methyl ester (7.5 mg, 0.059 mmol) weredissolved in DCM (2 ml). Diisopropyl ethyl amine (27 □l, 0.158 mmol) andTBTU (15 mg, 0.047 mmol) were added successively and the mixture wasstirred for 2 hours at ambient temperature. The crude product waspurified by flash chromatography using DCM/EtOAc (8/2) as eluent 79%yield (22 mg). M/z 710.

Method 89

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxyethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium hydroxide (38 mg, 0.95 mmol) was dissolved in ethanol (2.5 ml)and then1,1-Dioxo-3-butyl-73-ethyl-5-phenyl-7-bromo-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 96/16051; 200 mg, 0.443 mmol) was added. After stirring at roomtemperature for 5 min, 3-bromopropionic acid (68 mg, 0.443 mmol) wasadded and the reaction mixture was refluxed for 20 hours. Acetic acidwas added. The solvent was evaporated under reduced pressure and theresidue was extracted with EtOAc/water. The organic layer was separated,washed with water, dried and evaporated under reduced pressure. Thecrude product was purified by column chromatography using DCM/MeOH(100:5) as eluent to give the title compound 89 mg (38%). NMR (CD₃OD)0.75–0.83 (m, 6H), 1.0–1.25 (m, 4H), 1.38–1.65 (m, 4H), 2.82 (m, 2H),3.26 (s, 2H), 3.50–3.90 (m, 2H), 4.33 (t, 2H), 6.99 (t, 1H), 7.07–7.13(m, 3H), 7.28 (t, 2H), 7.53 (s, 1H).

Method 90

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-{N-[(R)-α-(t-butoxycarbonyl)benzyl]carbamoyl}ethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(2-carboxyethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 89; 70 mg, 0.134 mmol) and (R)-α-(t-butoxycarbonyl)benzylamine(J. Amer. Chem. Soc.; EN; 117; 44; 1995; 10879–10888; 35 mg, 0.169 mmol)in DCM (2.5 ml) was added 2,6-lutidine (29 mg, 0.268 mmol) and TBTU (56mg, 0.174 mmol). The reaction mixture was stirred at room temperaturefor 2.5 hours, then diluted with DCM. The solution was washed withNaHCO₃ (aq, sat), water, dried and the solvent was evaporated underreduced pressure. The residue was suspended in ether/petroleum ether andthe crystals filtered to give the title compound 85 mg (89%). NMR (500MHz) 0.79–0.86 (m, 6H), 1.04–1.28 (m, 4H), 1.35–1.56 (m, 11H), 1.60–1.77(m, 2H), 2.82 (t, 2H), 3.13–3.25 (m, 2H), 3.72 (brs, 2H), 4.35–4.44 (m,2H), 5.54 (d, 1H), 6.95 (d, 1H), 7.04 (t, 1H), 7.08 (d, 2H), 7.15 (s,1H), 7.29–7.43 (m, 6H), 7.52 (s, 1H).

Methods 91–94

The following compounds were synthesised by the procedure of Example 104using the appropriate starting material (source of amine indicated wherenot commercially available).

Meth Compound NMR(500MHz)and m/z SM 91

0.77–0.86(m, 6H), 1.03–1.62(m,21H), 2.21(s, 3H), 2.32(dd, 1H),2.54(dd,1H), 3.14(s, 2H), 3.74(brs, 2H), 4.48–4.53(m, 1H), 4.60(dd, 2H), 5.57(d,1H), 6.33(d,1H), 6.67(s, 1H), 7.01(t, 1H),7.09(d, 2H), 7.17–7.40(m,21H),7.50(d, 2H), 8.10(d, 1H);m/z 1040.83 Ex 1;¹ 92

0.78–0.86(m, 6H), 1.05–1.27(m,8H), 1.36–1.58(m, 13H), 1.78(s,3H),2.23(s, 3H), 2.77–2.92(m,2H), 3.19(s, 2H), 7.75(brs, 2H),4.64(dd, 2H),4.72–4.77(m, 1H),6.68(s, 1H), 6.81(d, 1H), 7.01(t,1H), 7.09(d, 2H),7.27–7.42(m,6H), 7.50(d, 2H), 8.16(d, 1H);m/z 812.23 Ex 1;² 93

0.74–0.81(m, 6H), 1.0–1.22(m,8H), 1.29–1.62(m, 13H), 2.13(s,3H),2.50–2.64(m, 2H), 3.14(s,2H), 3.69(brs, 2H), 4.42–4.48(m,1H), 4.58(dd,2H), 5.45(d, 1H),6.13(d, 1H), 6.62(s, 1H), 6.96(t,1H), 7.04(d, 2H),7.17–7.21(m,3H), 7.23–7.37(m, 18H), 7.41(d,2H), 8.0(d, 1H) Ex 1;Meth11394

0.81–0.87(m, 6H), 1.06–1.29(m,8H), 1.39–1.61(m, 4H), 1.78(brs,2H),1.94(s, 3H), 2.07–2.17(m,1H), 2.20–2.27(m, 4H), 3.31(s,2H), 3.77(brs,2H), 3.80(s, 3H),4.65(dd, 2H), 4.76–4.82(m, 1H),5.65–5.70(m, 1H),6.69(s, 1H),7.04(t, 1H), 7.12(d, 2H),7.29–7.44(m, 7H), 7.52(d,2H),8.16(d, 1H) Ex 1 ¹t-butyl L-(S-trityl)cysteinate hydrochloride: Org.Pre. Proced. Int.; 1999, 31: 571–572 ²S-methyl-L-cysteine tert-butylester: Pestic. Sci.; EN; 45; 4; 1995; 357–362Method 95

3,3-Dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

A mixture of3,3-dibutyl-4-oxo-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(WO 95/04534; 1.0 g, 2.5 mmol), 4-bromochlorobenzene (4.78 g, 24.98mmol), copper bromide (36 mg, 0.25 mmol) and potassium carbonate (0.35g, 2.5 mmol) was refluxed for 20 hours. The reaction mixture was loadedonto a column and the product eluted with 5% EtOAc/petroleum ether (0.8g, 63% yield). NMR (500 MHz) 0.86–0.92 (m, 6H), 1.16–1.35 (m, 8H),1.45–1.65 (m, 4H), 3.16 (s, 2H), 3.96 (s 3H), 7.06–7.10 (m, 2H), 7.19(s, 1H), 7.29 (s, 1H), 7.33–7.38 (m, 2H). M/z 511.

Method 96

1,1-Dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a mixture of3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 95; 0.67 g, 1.304 mmol), DCM (34 ml), water (34 ml) andpotassium carbonate (0.554 g, 4.0 mmol) was added at 0° C.m-chloroperoxybenzoic acid (0.78 g, 3.2 mmol) in one portion. Thereaction mixture was stirred at 0° C. for 10 h and then at roomtemperature for 14 hours. DCM (100 ml) and NaHCO₃ (aq, sat; 150 ml) wereadded. The organic layer was separated, washed with brine, dried andevaporated under reduced pressure to give the title compound 0.68 g(96%). NMR (600 MHz) 0.7–0.92 (m, 6H), 1.0–1.60 (m, 10H), 1.70–1.92 (m,2H), 2.30–3.7 (m, 2H), 3.99 (s, 3H), 7.16–7.20 (m, 2H), 7.24 (s, 1H),7.34–7.37 (m, 2H), 7.44 (s, 1H); m/z 543.

Method 97

1,1-Dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Sodium methanethiolate (0.43 g, 6.08 mmol) was added to a solution of1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 96; 0.66 g, 1.22 mmol) in anhydrous DMF (11 ml) under nitrogen.The reaction mixture was stirred at room temperature for 72 hours. Thesolvent was evaporated under reduced pressure and the residue wasextracted with trichloromethane/water. The organic layer was separated,washed with brine, dried and evaporated under reduced pressure. Thecrude product was purified by column chromatography using DCM as eluentto give the title compound 0.6 g (96%). NMR (500 MHz) 0.80–1.0 (m, 6H),1.10–1.6 (m, 10H), 1.70–2.0 (m, 2H), 2.28 (s, 3H), 3.37–3.70 (m, 2H),4.04 (s, 3H), 6.65 (s, 1H), 7.25–7.30 (m, 2H), 7.35–7.42 (m, 3H); m/z510.4.

Method 98

1,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 97; 0.41 g, 0.79 mmol) in anhydrous ether (15 ml) was addedLiAlH₄ (0.15 g, 3.97 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 2.5 hours. The reaction flask was cooledto 0° C. and the excess LiAlH₄ was quenched by adding water (0.3 ml) and2 M aqueous NaOH (0.3 ml). The mixture was filtered and the filtrate wasdried and evaporated under reduced pressure. The crude product waspurified by column chromatography using DCM as eluent to give the titlecompound 0.265 g (68%). NMR (300 MHz) 0.8–0.90 (m, 6H), 1.0–1.47 (m,12H), 2.33 (s, 3H), 3.17 (s, 2H), 3.70 (s, 2H), 3.93 (s, 3H), 7.03–7.08(m, 3H), 7.23–7.32 (m, 3H); m/z 496.

Method 99

1,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 98; 0.26 g 0.52 mmol) in anhydrous DCM (10 ml) was added borontribromide (2.63 g, 10.48 mmol) under nitrogen. The reaction mixture wasstirred at room temperature for 2.5 h. The reaction flask was cooled to0° C., water (20 ml) and hydrazine monohydrate (0.5 ml) was added. Theorganic layer was separated, dried and evaporated under reducedpressure. The crude product was purified by column chromatography usingDCM/EtOAc (100:5 and 100:10) as eluent to give the title compound 0.20 g(80%). NMR (500 MHz) 0.85 (t, 6H), 1.03–1.28 (m, 8H), 1.35–1.46 (m, 4H),2.39 (s, 3H), 3.21 (s, 2H), 3.73 (s, 2H), 7.04 (d, 2H), 7.29–7.34 (m,3H), 7.44 (s, 1H); m/z 482.

Method 100

1,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

Ethyl bromoacetate (0.101 g, 0.604 mmol) was added to a mixture of1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 99; 0.194 g, 0.402 mmol), anhydrous Na₂CO₃ (0.192 g, 1.81 mmol)and tetrabutylammonium bromide in MeCN (5 ml). The reaction mixture wasrefluxed for 3.5 hours. The solvent was evaporated under reducedpressure and the residue was extracted with DCM/water. The organic layerwas separated, dried and evaporated under reduced pressure. The crudeproduct was purified by column chromatography using DCM/EtOAc (100:5 and100:10) as eluent to give the title compound 0.197 g (86%). NMR (300MHz) 0.80–0.89 (m, 6H), 1.0–1.45 (m, 15H), 2.34 (s, 3H), 3.16 (s, 2H),3.68 (s, 2H), 4.30 (q, 2H), 4.71 (s, 2H), 7.05–7.11 (m, 3H), 7.19 (s,1H), 7.29–7.35 (m, 2H).

Method 101

1,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 100; 0.195 g, 0.343 mmol) in ethanol (8 ml) was added NaOH (1.03mmol in 0.5 ml water). The reaction mixture was stirred at roomtemperature for 70 min and then quenched by adding acetic acid (0.3 ml).The solvent was evaporated under reduced pressure and the residue wasextracted with DCM/water. The organic layer was separated, washed withbrine, dried and evaporated under reduced pressure to give the titlecompound 0.169 g (91%). NMR (500 MHz, CD₃OD) 0.86 (t, 6H), 1.11–1.28 (m,8H), 1.37–1.44 (m, 4H), 2.33 (s, 3H), 3.25 (s, 2H), 3.55 (s, 2H), 4.73(s, 2H), 7.10–7.15 (m, 3H), 7.26 (s, 1H), 7.28–7.32 (m, 2H).

Method 102

1,1-Dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-[N-{(R)-α-[N′-(t-butoxycarbonylmethyl)carbamoyl]benzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a solution of1,1-dioxo-3,3-dibutyl-5-(4-chlorophenyl)-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 101; 100 mg, 0.185 mmol) and(R)-α-[N-(t-butoxycarbonylmethyl)carbamoyl]benzylamine (Method 86; 56mg, 0.213 mmol) in DCM (4 ml) was added 2,6-lutidine (40 mg, 0.37 mmol)and TBTU (89 mg, 0.28 mmol). The reaction mixture was stirred at roomtemperature for 2 hours and then EtOAc was added and the solution washedwith water. The organic layer was separated, dried and evaporated underreduced pressure. The crude product was purified by columnchromatography using DCM/MeOH (100:3) as eluent to give the titlecompound 0.129 g (89%). NMR (600 MHz) 0.78–82 (m, 6H), 1.01–1.23 (m,8H), 1.30–1.42 (m, 13H), 2.32 (s, 3H), 3.10–3.16 (m, 2H), 3.62–3.68 (m,2H), 3.81–3.87 (m, 1H), 3.95–4.03 (m, 1H), 4.52 (dd, 2H), 5.57 (d, 1H),6.27 (t, 1H), 7.01–7.07 (m, 3H), 7.20–7.43 (m, 8H), 8.02 (d, 1H).

Method 103

3,3-Dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To 3,3-dibutyl-4-oxo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(synthesised by the procedure of WO9616051 for the corresponding3-butyl-3-ethyl analogue; 2.9 g, 9.0 mmol) was addedp-nitrophenylbromide (24 g, 119 mmol), K₂CO₃ (1.6 g, 12 mmol) and CuI(180 mg, 0.95 mmol). The reaction mixture was heated to 200° C.overnight. Then it was allowed to cool down to room temperature and theresulting solid was purified by chromatography using DCM as eluent. Thefractions containing the product were concentrated under reducedpressure and EtOH (95%) was added and the insoluble p-nitrophenylbromidewas then filtered off. The residue was purified again by flashchromatography using DCM as eluent. The product was still not pure sothe residue was then purified by flash chromatography usingEtOAc:heptane, 1:9 as eluent to give the title compound 2.57 g (64%).NMR (600 MHz) 0.77–0.87 (m, 6H), 1.12–1.31 (m, 8H), 1.4–1.6 (m, 4H),3.09 (brs, 2H), 3.79 (s, 3H), 6.72–6.83 (m, 2H), 7.18–7.27 (m, 3H), 8.3(d, 2H).

Method 104

1,1-Dioxo-3,3-dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To3,3-dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 103; 2.57 g, 5.8 mmol) was added DCM (130 ml), water (130 ml)and K₂CO₃ (2.44 g, 17.6 mmol). The reaction mixture was cooled down to0° C. and m-chloroperoxybenzoic acid (3.42 g, 13.9 mmol) was added inone portion. The reaction was allowed to complete overnight with thetemperature slowly rising to room temperature. Then NaHCO₃aq (sat) wasadded and the two layers were separated. The water layer was thenextracted three times with DCM. The combined organic layers was dried,filtered and evaporated under reduced pressure. The product was purifiedby flash chromatography using DCM as eluent to give the title compound2.4 g (87%). M/z 475.4.

Method 105

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To LiAlH₄ (5.76 g, 151 mmol) were added THF (200 ml). The reactionmixture was cooled to 0° C. and H₂SO₄ (4.06 ml, 76 mmol) were addedslowly with a syringe. After the addition was completed the reaction wasstirred for 10 minutes, Then1,1-dioxo-3,3-dibutyl-4-oxo-5-(4-nitrophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 104; 2.57 g, 5.06 mmol) dissolved in THF (50 ml) was added at 0°C. After vigorous stirring for 1 hour the cooling bath was removed andthe reaction was heated to 40° C. overnight. Then Na₂SO₄.10H₂O (3–4teaspoons), water (8 ml), NaOH (15%, aq) (8 ml), water (25 ml) and MeOH(30 ml) were added in that order. The precipitate was removed byfiltration and rinsed with DCM/MeOH. The solvent was dried, filtered andconcentrated under reduced pressure. The residue was purified by flashchromatography using DCM:EtOAc, 9:1 then 3:1 as eluent to give the titlecompound 0.6 g (27%). M/z 431.3.

Method 106

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 105; 918 mg, 2.13 mmol) was dissolved in DMF (dry, 20 ml).Sodium thiomethoxide (810 mg, 11.6 mmol) was added. The reaction mixturewas treated at 100–120° C. for four hours then room temperatureovernight. Acetic acid (3 ml) was added and the mixture was flushed withnitrogen (g) and the gas was lead through a flask containing sodiumhypochlorite in order to destroy the methyl mercaptan formed. Water wasadded and the water layer was extracted two times with EtOAc. Thecombined organic layer was washed with brine, dried, filtered andevaporated under reduced pressure. The mixture contained DMF so tolueneand brine was added (everything didn't dissolved). The water layer wasextracted two times with toluene. The combined organic layers werewashed once with brine. The separation funnel was washed with EtOAc inorder to dissolve everything. The toluene and EtOAc solutions werecombined, dried, filtered and evaporated under reduced pressure. Theresidue was purified by flash chromatography using DCM:EtOAc, 7:3 aseluent to give the title compound 0.6 g (27%). M/z 417.4.

Method 107

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 106; 600 mg, 1.44 mmol was dissolved in THF (10 ml).Di-t-butyldicarbonate (314 mg, 1.44 mmol) was added and the mixture wasstirred at 60° C. for two hours and room temperature for 3 days. Thesolvent was evaporated under reduced pressure. EtOAc was added and theorganic layer was washed once with KHSO₄-solution (0.3M, aq) and oncewith brine, dried, filtered and evaporated under reduced pressure. Theresidue was purified by flash chromatography using DCM:EtOAc, 9:1 aseluent to give the title compound 0.597 g (80%). M/z 517.3.

Method 108

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepineMethod 107; 597 mg, 1.16 mmol) was dissolved in MeCN (20 ml), K₂CO₃ (480mg, 3.5 mmol), tetrabutylammoniumbromide (54 mg, 0.17 mmol) and ethylbromoacetate (167 μl, 1.5 mmol) was added. The mixture was heated to 60°C. overnight. The solvent was evaporated under reduced pressure. EtOAcand water was added and the water layer was extracted two times withEtOAc. The combined organic layer was washed once with brine, dried,filtered and evaporated under reduced pressure to give the titlecompound 0.617 g (89%). M/z 603.3.

Method 109

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 108; 607 mg, 1.0 mmol) was dissolved in THF (6 ml), H₂O (6 ml)and LiOH (127 mg, 3.02 mmol, monohydrate) was added. The mixture wasstirred for 1 hour. The mixture was poured into water and the solutionwas acidified using HCl-solution (aq, 1M). The water layer was extractedtwo times with EtOAc. The combined organic layer was wash once withbrine, dried, filtered and evaporated under reduced pressure to give thetitle compound 0.571 g (99%). M/z 575.4.

Method 110

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-t-butoxycarbonylaminophenyl)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 45; 562 mg, 0.78 mmol) was dissolved in DCM (18 ml). TFA (4 ml)was added and the reactions mixture was stirred for 3 hours. The solventwas evaporated under reduced pressure. The residue was partitionedbetween EtOAc and NaOH solution (1M, aq). The aqueous phase wasextracted one more time with EtOAc. The combined organic layer was washwith brine, dried, filtered and evaporated under reduced pressure togive the title compound 440 mg (91%). M/z 622.5.

Method 111

1,1-Dioxo-3,3-dibutyl-5-[4-(N′-t-butylureido)phenyl]-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3,3-dibutyl-5-(4-aminophenyl)-8-[N-(α-(R)-methoxycarbonylbenzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 110; 40mg, 0.064 mmole) was dissolved in DMF (1 ml). t-Butyl isocyanate (8.3μl, 0.071 mmol) was added. The reaction mixture was stirred at 60–80° C.overnight. Tert-butyl isocyanate (20 μl, 0.171 mmol) was added. Thereaction mixture was stirred at 60–80° C. for 2 days and then roomtemperature for a few days. The solvent was evaporated under reducedpressure. The product was purified by preparative HPLC using anMeCN/ammonium acetate buffer gradient (5/95 to 100/0) as eluent to givethe title product, 30 mg (65%). M/z 721.6.

Method 112

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-[N-(α-methoxycarbonylmethyl-benzyl)carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine

The title compound was synthesized from1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 17) and methyl 3-amino-3-phenylpropanoate (Helv. Chim. Acta; EN;83; 6; 2000; 1256–1267) by the procedure of Example 56. M/z 639.4.

Method 113

t-Butyl D-(S-trityl)cysteinate hydrochloride

To a vigorously stirred suspension of S-trityl-D-cysteine (2.0 g, 5.5mmol) in t-butyl acetate (35 ml), 70% HClO₄ (1.6 ml) was added dropwise.The reaction mixture was stirred at room temperature for 70 min andEtOAc (50 ml) and NaHCO₃ (aq, sat) to pH 8.0 were added. Theprecipitate, unreacted S-trityl-D-cysteine was filtered off. The organiclayer was separated, washed with 0.5 M HCl (2×75 ml) and brine, driedand evaporated to give the title compound 2.02 g (81%). NMR (500 MHz):1.43 (s, 9H), 2.83–2.95 (m, 2H), 3.41–3.48 (m, 1H), 7.21–7.37 (m, 9H),7.46 (d, 6H).

Method 114

1,1-Dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyl-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 26; 12.85 g, 28.71 mmol) in MeCN (150 ml) was added ethylbromoacetate (3.85 ml, 34.6 mmol), tetrabutylammonium bromide (0.925 g,2.869 mmol) and sodium carbonate (12.85 g, 121.2 mmol). The mixture washeated under reflux for 5 hours. The solvent was removed under reducedpressure and the residue was partitioned between DCM and 0.5 M HCl. Theorganic layer was washed with brine, dried (MgSO₄) and concentrated.Chromatography using DCM/EtOAc (9:1) as eluent gave the desired product(15.45 g) as a tan oil. NMR 0.70–0.85 (m, 6H), 1.00–1.55 (m, 15H), 2.15(s, 3H), 3.10 (s, 2H), 3.70 (bs, 2H), 4.25 (q, 2H), 4.70 (s, 2H), 6.65(s, 1H), 6.90–7.30 (m, 6H).

Method 115

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 116; 0.48 g, 1.04 mmol) was dissolved in ethanol (10 ml). NaOH(0.30 g, 7.5 mmol) was added and the mixture was refluxed for 30 min.Acetic acid (1 ml) was added. The solvent was evaporated under reducedpressure and the residue was extracted with DCM/water. The DCM layer wasseparated, dried and evaporated. 0.44 g (97%) of the title compound wasobtained. NMR (300 MHz) 0.7–0.8 (m, 6H), 1.0–1.6 (m, 8H), 3.1–3.3 (m,2H), 3.5–3.8 (m, 2H), 4.6 (s, 3H), 6.8–7.3 (m, 7H), 7.5 (s, 1H).

Method 116

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepin(WO9616051; 0.40 g, 1.07 mmol), ethyl bromoacetate (0.23 g, 1.38 mmol),sodium carbonate (0.50 g, 4.7 mmol) and tetrabutylammonium bromide (30mg, 0.093 mmol) were added to MeCN (10 ml). The mixture was refluxed for18 hours and then evaporated under reduced pressure. The residue wasextracted with DCM/water. The DCM layer was separated and evaporatedunder reduced pressure. The residue was purified by columnchromatography. The product was eluted with DCM/EtOAc (90:10). 0.480 g(97%) of the title compound was obtained. NMR (300 MHz) 0.7–0.85 (m,6H), 1.0–1.7 (m, 11H), 3.1–3.3 (m, 2H), 3.6–3.8 (m, 2H), 4.3 (q, 2H),4.6 (s, 2H), 6.9–7.3 (m, 7H), 7.5 (d, 1H).

Method 117

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of1,1-dioxo-3,3-dipropyl-5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(prepared according to WO 96/16051 using identical synthetic stepsexcept that the starting material was chosen to give the dipropylcompound instead of the butyl/ethyl compound; 0.756 g, 1.62 mmol) in DMF(40 ml) was added NaSMe (0.605 g, 8.20 mmol, 95%), and the mixture wasstirred over night at 120° C. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc and 0.5 M HCl.The aqueous layer was extracted twice more with EtOAc and the combinedorganic extracts were dried (MgSO₄) and concentrated. The title compoundwas obtained in 0.665 g (98%). NMR (500 MHz, DMSO-d₆) 0.60–0.80 (m, 6H),1.05–1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s, 2H), 3.65 (brs, 2H), 6.65 (s,1H), 6.75–6.95 (m, 3H), 7.10–7.25 (m, 2H), 7.30 (s, 1H), 10.5 (s, 1H).

Method 118

1,1-Dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-carboxymethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine

To a suspension of1,1-dioxo-3,3-dipropyl-5-phenyl-7-methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,5-benzothiazepine(Method 117; 0.665 g, 1.58 mmol) in MeCN (10 ml) was added ethylbromoacetate (0.262 ml, 2.35 mmol), tetrabutylammonium bromide (0.051 g,0.158 mmol) and sodium carbonate (0.870 g, 8.21 mmol). The mixture wasstirred over night at 80° C. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc and 0.5 M HCl.The organic layer was washed with brine, dried (MgSO₄) and concentrated.The residue was filtered through a short silica column (DCM:EtOAc-9:1),concentrated and dissolved in EtOH (10 ml). A solution of NaOH (0.25 g,6.25 mmol) in water (1 ml) was added and the solution was stirred overnight at room temperature. The solvent was removed under reducedpressure and the residue was partitioned between EtOAc and 0.5 M HCl.The aqueous layer was extracted twice more with EtOAc and the combinedorganic extracts were washed with brine and concentrated. The crudeproduct was purified by preparative HPLC using a MeCN/ammonium acetatebuffer to give the title compound in 0.441 g (58%) as a white solid. NMR(DMSO-d₆) 0.55–0.75 (m; 6H), 1.05–1.50 (m, 8H), 2.15 (s, 3H), 3.20 (s,2H), 3.65 (brs, 2H), 4.50 (s, 2H), 6.65 (s, 1H), 6.80–7.00 (m, 3H), 7.15(s, 1H), 7.15–7.25 (m, 2H).

Example 121

The following illustrate representative pharmaceutical dosage formscontaining the compound of formula (I), or a pharmaceutically acceptablesalt, solvate, solvate of such a salt or a prodrug thereof (hereaftercompound X), for therapeutic or prophylactic use in humans:

(a): Tablet I mg/tablet Compound X 100 Lactose Ph. Eur 182.75Croscarmellose sodium 12.0 Maize starch paste (5% w/v paste) 2.25Magnesium stearate 3.0

(b): Tablet II mg/tablet Compound X 50 Lactose Ph. Eur 223.75Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/vpaste) 2.25 Magnesium stearate 3.0

(c): Tablet III mg/tablet Compound X 1.0 Lactose Ph. Eur 93.25Croscarmellose sodium 4.0 Maize starch paste (5% w/v paste) 0.75Magnesium stearate 1.0

(d): Capsule mg/capsule Compound X 10 Lactose Ph. Eur 488.5 Magnesiumstearate 1.5

(e): Injection I (50 mg/ml) Compound X  5.0% w/v 1 M Sodium hydroxidesolution 15.0% v/v 0.1 M Hydrochloric acid (to adjust pH to 7.6)Polyethylene glycol 400  4.5% w/v Water for injection to 100%

(f): Injection II 10 mg/ml Compound X  1.0% w/v Sodium phosphate BP 3.6% w/v 0.1 M Sodium hydroxide solution 15.0% v/v Water for injectionto 100%

(g): Injection III (1 mg/ml, buffered to pH 6) Compound X  0.1% w/vSodium phosphate BP 2.26% w/v Citric acid 0.38% w/v Polyethylene glycol400  3.5% w/v Water for injection to 100%Note

The above formulations may be obtained by conventional procedures wellknown in the pharmaceutical art. The tablets (a)–(c) may be entericcoated by conventional means, for Example to provide a coating ofcellulose acetate phthalate.

1. A compound of formula (I):

wherein: R^(v) and R^(w) are independently selected from hydrogen orC₁₋₆alkyl; R¹ and R² are independently selected from C₁₋₆alkyl; R^(x)and R^(y) are independently selected from hydrogen or C₁₋₆alkyl, or oneof R^(x) and R^(y) is hydrogen or C₁₋₆alkyl and the other is hydroxy orC₁₋₆alkoxy; R^(z) is selected from halo, nitro, cyano, hydroxy, amino,carboxy, carbamoyl, mercapto, sulphamoyl, C₁₋₆alkyl, C₂₋₆alkenyl,C₂₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkanoyl, C₁₋₆alkanoyloxy,N—(C₁₋₆alkyl)amino, N,N—(C₁₋₆alkyl)₂amino, C₁₋₆alkanoylamino,N—(C₁₋₆alkyl)carbamoyl, N,N—(C₁₋₆alkyl)₂carbamoyl, C₁₋₆alkylS(O)_(a)wherein a is 0 to 2, C₁₋₆alkoxycarbonyl, C₁₋₆alkoxycarbonylamino,ureido, N′—(C₁₋₆alkyl)ureido, N—(C₁₋₆alkyl)ureido,N′,N′—(C₁₋₆alkyl)₂ureido, N′—(C₁₋₆alkyl)-N—(C₁₋₆alkyl)ureido,N′,N′—(C₁₋₆alkyl)₂-N—(C₁₋₆alkyl)ureido, N—(C₁₋₆alkyl)sulphamoyl andN,N—(C₁₋₆alkyl)₂sulphamoyl; v is 0–5; one of R⁴ and R⁵ is a group offormula (IA):

R³ and R⁶ and the other of R⁴ and R⁵ are independently selected fromhydrogen, halo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl,mercapto, sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl andN,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R³ and R⁶ and the other of R⁴ and R⁵may be optionally substituted on carbon by one or more R¹⁶; D is —O—,—N(R^(a))—, —S(O)_(b)— or —CH(R^(a))—; wherein R^(a) is hydrogen orC₁₋₆alkyl and b is 0–2; Ring A is aryl or heteroaryl; wherein Ring A isoptionally substituted by one or more substituents selected from R¹⁷; R⁷is hydrogen, C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R⁷ isoptionally substituted by one or more substituents selected from R¹⁸; R⁸is hydrogen or C₁₋₄alkyl; R⁹ is hydrogen or C₁₋₄alkyl; R¹⁰ is hydrogen,C₁₋₄alkyl, carbocyclyl or heterocyclyl; wherein R¹⁰ is optionallysubstituted by one or more substituents selected from R¹⁹; R¹¹ iscarboxy, sulpho, sulphino, phosphono, tetrazolyl, —P(O)(OR^(c))(OR^(d)),—P(O)(OH)(OR^(c)), —p(O)(OH)(R^(d)) or —P(O)(OR^(c))(R^(d)) whereinR^(c) and R^(d) are independently selected from C₁₋₆alkyl; or R¹¹ is agroup of formula (IB):

wherein: X is —N(R^(q))—, —N(R^(q))C(O)—, —O—, and —S(O)_(a)—; wherein ais 0–2 and R^(q) is hydrogen or C₁₋₄alkyl; R¹² is hydrogen or C₁₋₄alkyl;R¹³ and R¹⁴ are independently selected from hydrogen, C₁₋₄alkyl,carbocyclyl, heterocyclyl or R²³; wherein said C₁₋₄alkyl, carbocyclyl orheterocyclyl may be independently optionally substituted by one or moresubstituents selected from R²⁰; R¹⁵ is carboxy, sulpho, sulphino,phosphono, tetrazolyl, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)),—P(O)(OH)(R^(e)) or —P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) areindependently selected from C₁₋₆alkyl; or R¹⁵ is a group of formula(IC):

wherein: R²⁴ is selected from hydrogen or C₁₋₄alkyl; R²⁵ is selectedfrom hydrogen, C₁₋₄alkyl, carbocyclyl, heterocyclyl or R²⁷; wherein saidC₁₋₄alkyl, carbocyclyl or heterocyclyl may be independently optionallysubstituted by one or more substituents selected from R²⁸; R²⁶ isselected from carboxy, sulpho, sulphino, phosphono, tetrazolyl,—P(O)(OR^(g))(OR^(h)), —P(O)(OH)(OR^(g)), —P(O)(OH)(R^(g)) or—P(O)(OR^(g))(R^(h)) wherein R^(g) and R^(h) are independently selectedfrom C₁₋₆alkyl; p is 1–3; wherein the values of R¹³ may be the same ordifferent; q is 0–1; r is 0–3; wherein the values of R¹⁴ may be the sameor different; m is 0–2; wherein the values of R¹⁰ may be the same ordifferent; n is 1–3; wherein the values of R⁷ may be the same ordifferent; z is 0–3; wherein the values of R²⁵ may be the same ordifferent; R¹⁶, R¹⁷ and R¹⁸ are independently selected from halo, nitro,cyano, hydroxy, amino, carboxy, carbamoyl, mercapto, sulphamoyl,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, C₁₋₄alkanoyl,C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino, N,N—(C₁₋₄alkyl)₂amino,C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl, N,N—(C₁₋₄alkyl)₂carbamoyl,C₁₋₄alkylS(O)_(a) wherein a is 0 to 2, C₁₋₄alkoxycarbonyl,N—(C₁₋₄alkyl)sulphamoyl and N,N—(C₁₋₄alkyl)₂sulphamoyl; wherein R¹⁶, R¹⁷and R¹⁸ may be independently optionally substituted on carbon by one ormore R²¹; R¹⁹, R²⁰, R²³, R²⁷ and R²⁸ are independently selected fromhalo, nitro, cyano, hydroxy, amino, carboxy, carbamoyl, mercapto,sulphamoyl, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy,C₁₋₄alkanoyl, C₁₋₄alkanoyloxy, N—(C₁₋₄alkyl)amino,N,N—(C₁₋₄alkyl)₂amino, C₁₋₄alkanoylamino, N—(C₁₋₄alkyl)carbamoyl,N,N—(C₁₋₄alkyl)₂carbamoyl, C₁₋₄alkylS(O)_(a) wherein a is 0 to 2,C₁₋₄alkoxycarbonyl, N—(C₁₋₄alkyl)sulphamoyl, N,N—(C₁₋₄alkyl)₂sulphamoyl,carbocyclyl, heterocyclyl, sulpho, sulphino, amidino, phosphono,—P(O)(OR^(a))(OR^(b)), P(O)(OH)(OR^(a)), P(O)(OH)(R^(a)) or—P(O)(OR^(a))(R^(b)), wherein R^(a) and R^(b) independently selectedfrom C₁₋₆alkyl; wherein R¹⁹, R²⁰, R²³, R²⁷ and R²⁸ may be independentlyoptionally substituted on carbon by one or more R²²; R²¹ and R²² areindependently selected from halo, hydroxy, cyano, carbamoyl, ureido,amino, nitro, carboxy, carbamoyl, mercapto, sulphamoyl, trifluoromethyl,trifluoromethoxy, methyl, ethyl, methoxy, ethoxy, vinyl, allyl, ethynyl,methoxycarbonyl, formyl, acetyl, formamido, acetylamino, acetoxy,methylamino, dimethylamino, N-methylcarbamoyl, N,N-dimethylcarbamoyl,methylthio, methylsulphinyl, mesyl, N-methylsulphamoyl andN,N-dimethylsulphamoyl; or a pharmaceutically acceptable salt, solvate,solvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 2. A compound of formula (I)according to claim 1 wherein R^(v) and R^(w) are both hydrogen or apharmaceutically acceptable salt, solvate, solvate of such a salt, or anin vivo hydrolysable ester formed on an available carboxy or hydroxythereof, or an in vivo hydrolysable amide formed on an available carboxythereof.
 3. A compound of formula (I) according to either of claims 1wherein R¹ and R² are independently selected from ethyl, propyl or butylor a pharmaceutically acceptable salt, solvate, solvate of such a salt,or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.
 4. A compound of formula (I) according to claim 1wherein R^(x) and R^(y) are both hydrogen or a pharmaceuticallyacceptable salt, solvate or solvate of such a salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof. 5.A compound of formula (I) according to claim 1 wherein R^(Z) is selectedfrom halo, amino, C₁₋₆alkyl, C₁₋₆alkoxycarbonylamino orN′—(C₁₋₆alkyl)ureido or a pharmaceutically acceptable salt, solvate orsolvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 6. A compound of formula (I)according to claim 1 wherein v is 0 or 1 or a pharmaceuticallyacceptable salt, solvate or solvate of such a salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof. 7.A compound of formula (I) according to claim 1 wherein R³ is hydrogen ora pharmaceutically acceptable salt, solvate or solvate of such a salt,or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.
 8. A compound of formula (I) according to claim 1wherein the R⁴ or R⁵ that is not the group of formula (IA) is selectedfrom hydrogen, halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein a is 0 to2; wherein that R₄ or R₅ may be optionally substituted on carbon by oneor more R¹⁶; wherein R¹⁶ is independently selected from hydroxy, carboxyand N,N—(C₁₋₄alkyl)₂amino or a pharmaceutically acceptable salt, solvateor solvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 9. A compound of formula (I)according to claim 1 wherein R⁵ is a group of formula (IA) (as depictedin claim 1) and R⁴ is methylthio or a pharmaceutically acceptable salt,solvate or solvate of such a salt, or an in vivo hydrolysable esterformed on an available carboxy or hydroxy thereof, or an in vivohydrolysable amide formed on an available carboxy thereof.
 10. Acompound of formula (I) according to claim 1 wherein R⁶ is hydrogen or apharmaceutically acceptable salt, solvate or solvate of such a salt, oran in vivo hydrolysable ester formed on an available carboxy or hydroxythereof, or an in vivo hydrolysable amide formed on an available carboxythereof.
 11. A compound of formula (I) according to claim 1 wherein inthe group of formula (IA): D is —O— or —S—; Ring A is phenyl, thienyl orindolyl; wherein Ring A is optionally substituted by one or moresubstituents selected from halo, hydroxy, methoxy or trifluoromethyl; R⁷is hydrogen, methyl or phenyl; R⁸ is hydrogen or methyl; R⁹ hydrogen ormethyl; R¹⁰ is hydrogen; m is 0–2 wherein the values of R¹⁰ may be thesame or different; and R¹¹ is carboxy, —P(O)(OH)(OEt) or a group offormula (IB) (as depicted in claim 1); or a pharmaceutically acceptablesalt, solvate or solvate of such a salt, or an in vivo hydrolysableester formed on an available carboxy or hydroxy thereof, or an in vivohydrolysable amide formed on an available carboxy thereof.
 12. Acompound of formula (I) according to claim 1 wherein in the group offormula (IB): R¹² is hydrogen or methyl; R¹³ is hydrogen, methyl, ethyl,butyl or phenyl or R²³; wherein R¹³ is optionally substituted by one ormore substituents selected from R²⁰; R²⁰ is hydroxy, methylthio,methoxy, amino, imidazolyl or mercapto; wherein R²⁰ may be independentlyoptionally substituted on carbon by one or more hydroxy; R²³ is carboxy;X is —NH— or —NHC(O)—; R¹⁴ is selected from hydrogen, methyl or phenyl;wherein said methyl or phenyl may be optionally substituted by one ormore substituents selected from hydroxy; R¹⁵ is carboxy, sulpho,phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or—P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selectedfrom methyl or ethyl or R¹⁵ is a group of formula (IC) (as depicted inclaim 1); p is 1–3 wherein the values of R¹³ may be the same ordifferent; q is 0–1; and r is 0–3 wherein the values of R¹⁴ may be thesame or different; or a pharmaceutically acceptable salt, solvate orsolvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 13. A compound of formula (I)according to claim 1 wherein in the group of formula (IC): R²⁴ ishydrogen; R²⁵ is hydrogen; R²⁶ is carboxy; and z is 1; or apharmaceutically acceptable salt, solvate or solvate of such a salt, oran in vivo hydrolysable ester formed on an available carboxy or hydroxythereof, or an in vivo hydrolysable amide formed on an available carboxythereof.
 14. A compound of formula (I) according to claim 1 wherein:R^(v) and R^(w) are both hydrogen; R¹ and R² are independently selectedfrom C₁₋₄alkyl; R^(x) and R^(y) are both hydrogen; R^(z) is selectedfrom halo, amino, C₁₋₆alkyl, C₁₋₆alkoxycarbonylamino orN′—(C₁₋₆alkyl)ureido; v is 0 or 1; R³ and R⁶ are hydrogen; one of R⁴ andR⁵ is a group of formula (IA) (as depicted in claim 1) and the other isselected from hydrogen, halo, C₁₋₄alkoxy or C₁₋₄alkylS(O)_(a) wherein ais 0 to 2; wherein that R⁴ or R⁵ may be optionally substituted on carbonby one or more R¹⁶; wherein R¹⁶ is independently selected from hydroxy,carboxy and N,N—(C₁₋₄alkyl)₂amino; D is —O— or —S—; R⁷ is hydrogen,methyl or phenyl; R⁸ is hydrogen or methyl; Ring A is aryl orheteroaryl; wherein Ring A is optionally substituted by one or moresubstituents selected from R¹⁷; wherein R¹⁷ is selected from halo,hydroxy, C₁₋₄alkyl or C₁₋₄alkoxy; wherein R¹⁷ may be optionallysubstituted on carbon by one or more R²¹; wherein R²¹ is selected fromhalo; R⁹ hydrogen or methyl; R¹⁰ is hydrogen; R¹¹ is carboxy,—P(O)(OH)(OR^(c)) wherein R^(c) is selected from C₁₋₄alkyl or a group offormula (IB) (as depicted in claim 1); R¹² hydrogen or methyl; X is —NH—or —NHC(O)—; R¹³ is hydrogen, C₁₋₄alkyl, carbocyclyl or R²³; wherein R¹³is optionally substituted by one or more substituents selected from R²⁰;wherein R²⁰ is hydroxy, C₁₋₄alkylS(O)_(a) wherein a is 0, C₁₋₄alkoxy,amino, carbocyclyl, heterocyclyl or mercapto; wherein R²⁰ may beindependently optionally substituted on carbon by one or more R²²; R²²is selected from hydroxy; and R²³ is carboxy; R¹⁴ is selected fromhydrogen, C₁₋₄alkyl or carbocyclyl; wherein said C₁₋₄alkyl orcarbocyclyl may be optionally substituted by one or more substituentsselected from R²⁰; and R²⁰ is hydroxy; R¹⁵ is carboxy, sulpho,phosphono, —P(O)(OR^(e))(OR^(f)), —P(O)(OH)(OR^(e)), —P(O)(OH)(R^(e)) or—P(O)(OR^(e))(R^(f)) wherein R^(e) and R^(f) are independently selectedfrom C₁₋₄alkyl or R¹⁵ is a group of formula (IC) (as depicted in claim1); R²⁴ is hydrogen; R²⁵ is hydrogen; R²⁶ is carboxy; p is 1–3; whereinthe values of R¹³ may be the same or different; q is 0–1; r is 0–3;wherein the values of R¹⁴ may be the same or different; m is 0–2;wherein the values of R¹⁰ may be the same or different; n is 1–2;wherein the values of R⁷ may be the same or different; z is 0–1; whereinthe values of R²⁵ may be the same or different; or a pharmaceuticallyacceptable salt, solvate or solvate of such a salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof.15. A compound of formula (I) according to claim 1 selected from:1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-1′-phenyl-1′-[N′-(carboxymethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(carboxymethyl)-carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-1′-phenyl-1′-[N′-(2-sulphoethyl)carbamoyl]methyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N—{(R)-α-[N′-(2-sulphoethyl)carbamoyl]4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(2-carboxyethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(5-carboxypentyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(2-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N—{α-[N′-(2-sulphoethyl)carbamoyl]-2-fluorobenzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′{(R)-1-[N″—(R)-(2-hydroxy-1-carboxyethyl)carbamoyl]-2-hydroxyethyl}carbamoyl)benzyl]-carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-(carboxymethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-(N-{α-[N′-((ethoxy)(methyl)phosphoryl-methyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(hydroxy)(methyl)phosphoryl]ethyl}carbamoyl)benzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[N′-(2-methylthio-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(ethyl)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-{N—[(R)-α-(N′-{2-[(methyl)(hydroxy)phosphoryl]ethyl}carbamoyl)-4-hydroxybenzyl]carbamoylmethoxy}-2,3,4,5-tetrahydro-1,5-benzothiazepine;1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-N—{(R)-α-[(R)—N′-(2-methylsulphinyl-1-carboxyethyl)carbamoyl]benzyl}carbamoylmethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine;and1,1-dioxo-3,3-dibutyl-5-phenyl-7-methoxy-8-[N—{(R)-α-[N′-(2-sulphoethyl)carbamoyl]-4-hydroxybenzyl}carbamoylmethoxy]-2,3,4,5-tetrahydro-1,5-benzothiazepine;or a pharmaceutically acceptable salt, solvate, solvate of such a salt,or an in vivo hydrolysable ester formed on an available carboxy orhydroxy thereof, or an in vivo hydrolysable amide formed on an availablecarboxy thereof.
 16. A process for preparing a compound of the formula(I) according to claim 1 which comprises of: Process 1): oxidising abenzothiazepine of formula (II):

Process 2): for compounds of formula (I) wherein D is —O—, —NR^(a) or—S—; reacting a compound of formula (IIIa) or (IIIb):

with a compound of formula (IV):

wherein L is a displaceable group; Process 3): reacting an acid offormula (Va) or (Vb):

or an activated derivative thereof; with an amine of formula (VI):

Process 4): for compounds of formula (I) wherein R¹¹ is a group offormula (IB); reacting a compound of formula (I) wherein R¹¹ is carboxywith an amine of formula (VII):

Process 5): for compounds of formula (I) wherein R¹¹ is carboxy;deprotecting a compound of formula (VIIIa):

wherein R^(p) is C₁₋₄alkyl; Process 6): for compounds of formula (I)wherein R¹¹ is a group of formula (IB) and R¹⁵ is carboxy; deprotectinga compound of formula (IXa):

wherein R^(p) is C₁₋₄alkyl; Process 7) for compounds of formula (I)wherein one of R⁴ and R⁵ are independently selected from C₁₋₄alkylthiooptionally substituted on carbon by one or more R¹⁶; reacting a compoundof formula (Xa) or (Xb):

wherein L is a displaceable group; with a thiol of formula (XI):R^(y)—H  (XI) wherein R^(y) is C₁₋₄alkylthio optionally substituted oncarbon by one or more R¹⁶; Process 8) for compounds of formula (I)wherein R¹⁵ is a group of formula (IC) reacting a compound of formula(IXa) or (IXb) wherein R^(p) is hydrogen with a compound of formula(XII):

Process 9): for compounds of formula (I) wherein R¹¹ is a group offormula (IB) and R¹⁵ is a group of formula (IC) and R²⁶ is carboxy;deprotecting a compound of formula (XIIIa):

and R^(p) is C₁₋₄alkyl; Process 10): for compounds of formula (I)wherein X is —N(R^(q))C(O); reacting a compound of formula (XIVa):

with a compound of formula (XV):

and thereafter optionally: i) converting a compound of the formula (I)into another compound of the formula (I); ii) removing any protectinggroups; iii) forming a pharmaceutically acceptable salt, solvate,solvate of such a salt, or an in vivo hydrolysable ester formed on anavailable carboxy or hydroxy thereof, or an in vivo hydrolysable amideformed on an available carboxy thereof.
 17. A pharmaceutical compositionwhich comprises a compound of formula (I), or a pharmaceuticallyacceptable salt, solvate, solvate of such a salt, or an in vivohydrolysable ester formed on an available carboxy or hydroxy thereof, oran in vivo hydrolysable amide formed on an available carboxy thereof asclaimed in any one of claims 1 to 15, in association with apharmaceutically-acceptable diluent or carrier.
 18. A compound offormula (VIIIa), (VIIIb), (IXa), (IXb), (XIIIa) or (XIIIb) as defined inclaim 16 or a pharmaceutically acceptable salt, solvate or solvate orsuch a salt, or an in vivo hydrolysable ester formed on an availablecarboxy or hydroxy thereof, or an in vivo hydrolysable amide formed onan available carboxy thereof.